Inhibitors of 11-beta-hydroxy steroid dehydrogenase type 1

ABSTRACT

The present invention relates to compounds with the formula (I)  
                 
 
     and also to pharmaceutical compositions comprising the compounds, as well as to the use of the compounds in medicine and for the preparation of a medicament which acts on the human 11-β-hydroxysteroid dehydrogenase type 1 enzyme.

RELATED APPLICATIONS

[0001] This application claims priority to Swedish application number0103913-0, filed on Nov. 22, 2001, Swedish application number 0104051-8,filed on Nov. 30, 2001, and U.S. provisional application No. 60/348,468,filed on Jan. 14, 2002, the contents of which are incorporated herein byreference.

TECHNICAL FIELD

[0002] The present invention relates to novel compounds, topharmaceutical compositions comprising the compounds, as well as to theuse of the compounds in medicine and for the preparation of a medicamentwhich acts on the human 11-β-hydroxysteroid dehydrogenase type 1 enzyme(11βHSD1).

BACKGROUND

[0003] 1. Glucorticoids, Diabetes and Hepatic Glucose Production

[0004] It has been known for more than half a century thatglucocorticoids have a central role in diabetes, e.g. the removal of thepituitary or the adrenal gland from a diabetic animal alleviates themost severe symptoms of diabetes and lowers the concentration of glucosein the blood (Long, C. D. and F. D. W. Leukins (1936) J. Exp. Med. 63:465-490; Houssay, B. A. (1942) Endocrinology 30: 884-892). It is alsowell established that glucocorticoids enable the effect of glucagon onthe liver.

[0005] The role of 11βHSD1 as an important regulator of localglucocorticoid effect and thus of hepatic glucose production is wellsubstantiated (see e.g. Jamieson et al. (2000) J. Endocrinol. 165: p.685-692). The hepatic insulin sensitivity was improved in healthy humanvolunteers treated with the non-specific 11βHSD1 inhibitor carbenoxolone(Walker, B. R. et al. (1995) J. Clin. Endocrinol. Metab. 80: 3155-3159).Furthermore, the expected mechanism has been established by differentexperiments with mice and rats. These studies showed that the mRNAlevels and activities of two key enzymes in hepatic glucose productionwere reduced, namely: the rate-limiting enzyme in gluconeogenesis,phosphoenolpyruvate carboxykinase (PEPCK), and glucose-6-phosphatase(G6Pase) catalyzing the last common step of gluconeogenesis andglycogenolysis. Finally, the blood glucose level and hepatic glucoseproduction is reduced in mice having the 11βHSD1 gene knocked-out. Datafrom this model also confirm that inhibition of 11βHSD1 will not causehypoglycemia, as predicted since the basal levels of PEPCK and G6Paseare regulated independently of glucocorticoids (Kotelevtsev, Y. et al.,(1997) Proc. Natl. Acad. Sci. USA 94: 14924-14929).

[0006] Arzneim.-Forsch./Drug Res; 44 (II), No. 7, 821-826, 1994,discloses the hypoglycemic compounds4-(3-methyl-5-oxo-2-pyrazolin-1-yl)benzoic acid and1-(mesitylen-2-sulfonyl)-1H-1,2,4-triazole. The structures of thesecompounds differ considerably from the structure of the compounds of thepresent invention, in that the latter are thiadiazoles having an(hetero)arylsulfonamido substituent.

[0007] Merck & Co, Merck Index; Monograph number 4488 discloses theantidiabetic compoundN-(5-tert-butyl-1,3,4-thiadiazol-2-yl)benzenesulfonamide. The structureof this compound differs from the structure of the compounds of thepresent invention, in that the latter may not have a tert-butyl groupconnected directly to the thiadiazole ring.

[0008] FR 2,384,498 discloses compounds having a high hypoglycemiceffect. Therefore, treatment of hyperglycemia with these compounds maylead to hypoglycemia.

[0009] 2. Possible Reduction of Obesity and Obesity RelatedCardiovascular Risk Factors

[0010] Obesity is an important factor in syndrome X as well as in themajority (>80%) of type 2 diabetic, and omental fat appears to be ofcentral importance. Abdominal obesity is closely associated with glucoseintolerance, hyperinsulinemia, hypertriglyceridemia, and other factorsof the so-called syndrome X (e.g. raised blood pressure, decreasedlevels of HDL and increased levels of VLDL) (Montague & O'Rahilly,Diabetes 49: 883-888, 2000). Inhibition of the enzyme in pre-adipocytes(stromal cells) has been shown to decrease the rate of differentiationinto adipocytes. This is predicted to result in diminished expansion(possibly reduction) of the omental fat depot, i.e. reduced centralobesity (Bujalska, I. J., S. Kumar, and P. M. Stewart (1997) Lancet 349:1210-1213).

[0011] Inhibition of 11βHSD1 in mature adipocytes is expected toattenuate secretion of the plasminogen activator inhibitor 1 (PAI-1)—anindependent cardiovascular risk factor (Halleux, C. M. et al. (1999) J.Clin. Endocrinol. Metab. 84: 4097-4105). Furthermore, there is a clearcorrelation between glucocorticoid “activity” and cardiovascular riskfactore suggesting that a reduction of the glucocorticoid effects wouldbe beneficial (Walker, B. R. et al. (1998) Hypertension 31: 891-895;Fraser, R. et al. (1999) Hypertension 33: 1364-1368).

[0012] Adrenalectomy attenuates the effect of fasting to increase bothfood intake and hypothalamic neuropeptide Y expression. This supportsthe role of glucocorticoids in promoting food intake and suggests thatinhibition of 11βHSD1 in the brain might increase satiety and thereforereduce food intake (Woods, S. C. et al. (1998) Science, 280: 1378-1383).

[0013] 3. Possible Beneficial Effect on the Pancreas

[0014] Inhibition of 11βHSD1 in isolated murine pancreatic β-cellsimproves the glucose-stimulated insulin secretion (Davani, B. et al.(2000) J. Biol. Chem. 2000 Nov. 10; 275(45): 34841-4). Glucocorticoidswere previously known to reduce pancreatic insulin release in vivo(Billaudel, B. and B. C. J. Sutter (1979) Horm. Metab. Res. 11:555-560). Thus, inhibition of 11βHSD1 is predicted to yield otherbeneficial effects for diabetes treatment, besides effects on liver andfat.

[0015] 4. Possible Beneficial Effects on Cognition and Dementia

[0016] Stress and glucocorticoids influence cognitive function (deQuervain, D. J. -F., B. Roozendaal, and J. L. McGaugh (1998) Nature 394:787-790). The enzyme 11βPHSD1 controls the level of glucocorticoidaction in the brain and thus contributes to neurotoxicity (Rajan, V., C.R. W. Edwards, and J. R. Seckl, J. (1996) Neuroscience 16: 65-70; Seckl,J. R., Front. (2000) Neuroendocrinol. 18: 49-99). Unpublished resultsindicate significant memory improvement in rats treated with anon-specific 11βPHSD1 inhibitor (J. Seckl, personal communication).Based the above and on the known effects of glucocorticoids in thebrain, it may also be suggested that inhibiting 11βHSD1 in the brain mayresult in reduced anxiety (Tronche, F. et al. (1999) Nature Genetics 23:99-103). Thus, taken together, the hypothesis is that inhibition of11βHSD1 in the human brain would prevent reactivation of cortisone intocortisol and protect against deleterious glucocorticoid-mediated effectson neuronal survival and other aspects of neuronal function, includingcognitive impairment, depression, and increased appetite (previoussection).

[0017] WO 98/27081 and WO 99/02502 disclose 5HT₆ receptor antagonistsfor the treatment of CNS disorders. None of these compounds fall withinformula (I) according to the present invention. Furthermore, nothing issaid about the activity on 11βHSD1.

[0018] 5. Possible Use of Immuno-Modulation Using 11βHSD1 Inhibitors

[0019] The general perception is that glucocorticoids suppress theimmune system. But in fact there is a dynamic interaction between theimmune system and the HPA (hypothalamo-pituitary-adrenal) axis (Rook, G.A. W. (1999) Baillier's Clin. Endocrinol. Metab. 13: 576-581). Thebalance between the cell-mediated response and humoral responses ismodulated by glucocorticoids. A high glucocorticoid activity, such as ata state of stress, is associated with a humoral response. Thus,inhibition of the enzyme 11βHSD1 has been suggested as a means ofshifting the response towards a cell-based reaction.

[0020] In certain disease states, including tuberculosis, lepra andpsoriasis the immune reaction is normaly biased towards a humoralresponse when in fact the appropriate response would be cell based.Temporal inhibition of 11βHSD1, local or systemic, might be used to pushthe immune system into the appropriate response (Mason, D. (1991)Immunology Today 12: 57-60; Rook et al., supra).

[0021] An analogous use of 11βHSD1 inhibition, in this case temporal,would be to booster the immune response in association with immunizationto ensure that a cell based response would be obtained, when desired.

[0022] 6. Reduction of Intraocular Pressure

[0023] Recent data suggest that the levels of the glucocorticoid targetreceptors and the 11βHSD enzymes determines the susceptibility toglaucoma (Stokes, J. et al. (2000) Invest. Ophthalmol. 41: 1629-1638).Further, inhibition of 11βHSD1 was recently presented as a novelapproach to lower the intraocular pressure (Walker E. A. et al, posterP3-698 at the Endocrine society meeting Jun. 12-15, 1999, San Diego).Ingestion of carbenoxolone, a non-specific inhibitor of 11βHSD1, wasshown to reduce the intraocular pressure by 20% in normal subjects. Inthe eye, expression of 11βHSD1 is confined to basal cells of the cornealepithelium and the non-pigmented epithelialium of the cornea (the siteof aqueous production), to ciliary muscle and to the sphincter anddilator muscles of the iris. In contrast, the distant isoenzyme 11βHSD2is highly expressed in the non-pigmented ciliary epithelium and cornealendothelium. None of the enzymes is found at the trabecular meshwork,the site of drainage. Thus, 11βHSD1 is suggested to have a role inaqueous production, rather than drainage, but it is presently unknown ifthis is by interfering with activation of the glucocorticoid or themineralocorticoid receptor, or both.

[0024] 7. Reduced Osteoporosis

[0025] Glucocorticoids have an essential role in skeletal developmentand function but are detrimental in excess. Glucocorticoid-induced boneloss is derived, at least in part, via inhibition of bone formation,which includes suppression of osteoblast proliferation and collagensynthesis (Kim, C. H., S. L. Cheng, and G. S. Kim (1999) J. Endocrinol.162: 371-379). The negative effect on bone nodule formation could beblocked by the non-specific inhibitor carbenoxolone suggesting animportant role of 11βHSD1 in the glucocorticoid effect (Bellows, C. G.,A. Ciaccia, and J. N. M. Heersche, (1998) Bone 23: 119-125). Other datasuggest a role of 11βHSD1 in providing sufficiently high levels ofactive glucocorticoid in osteoclasts, and thus in augmenting boneresorption (Cooper, M. S. et al. (2000) Bone 27: 375-381). Takentogether, these different data suggest that inhibition of 11PHSD1 mayhave beneficial effects against osteoporosis by more than one mechanismworking in parallel.

[0026] 8. Reduction of Hypertension

[0027] Bile acids inhibit 11β-hydroxysteroid dehydrogenase type 2. Thisresults in a shift in the overall body balance in favour of cortisolover cortisone, as shown by studying the ratio of the urinarymetabolites (Quattropani C, Vogt B, Odermatt A, Dick B, Frey B M, Frey FJ. 2001. J Clin Invest. November; 108(9): 1299-305. “Reduced activity of11beta-hydroxysteroid dehydrogenase in patients with cholestasis”.).Reducing the activity of 11bHSD1 in the liver by a selective inhibitoris predicted to reverse this imbalance, and acutely counter the symptomssuch as hypertension, while awaiting surgical treatment removing thebiliary obstruction.

[0028] WO 99/65884 discloses carbon substituted aminothiazole inhibitorsof cyclin dependent kinases. These compounds may e.g. be used againstcancer, inflammation and arthritis. U.S. Pat. No. 5,856,347 discloses anantibacterial preparation or bactericide comprising 2-aminothiazolederivative and/or salt thereof. Further, U.S. Pat. No. 5,403,857discloses benzenesulfonamide derivatives having 5-lipoxygenaseinhibitory activity. Additionally, tetrahydrothiazolo[5,4-c]pyridinesare disclosed in: Analgesic tetrahydrothiazolo[5,4-c]pyridines. Fr.Addn. (1969), 18 pp, Addn. to Fr. 1498465. CODEN: FAXXA3; FR 9412319690704 CAN 72:100685 AN 1970:100685 CAPLUS and4,5,6,7-Tetrahydrothiazolo[5,4-c]pyridines. Neth. Appl. (1967), 39 pp.CODEN: NAXXAN NL 6610324 19670124 CAN 68:49593, AN 1968: 49593 CAPLUS.However, none of the above disclosures discloses the compounds accordingto the present invention, or their use for the treatment of diabetes,obesity, glaucoma, osteoporosis, cognitive disorders, immune disorders,depression, and hypertension.

[0029] WO 98/16520 discloses compounds inhibiting matrixmetalloproteinases (MMPs) and TNF-α converting enzyme (TACE). EP 0 749964 A1 and U.S. Pat. No. 5,962,490 disclose compounds having anendothelin receptor antagonist activity. None of these compounds fallwithin formula (I) according to the present invention. Furthermore,nothing is said about the activity on 11βHSD1.

[0030] U.S. Pat. No. 5,783,697 discloses thiophene derivatives asinhibitors of PGE2 and LTB4. Nothing is said about the activity on11βHSD1.

[0031] Consequently, there is a need of new compounds that are useful inthe treatment of diabetes, obesity, glaucoma, osteoporosis, cognitivedisorders, immune disorders, depression, and hypertension.

SUMMARY OF THE INVENTION

[0032] The compounds according to the present invention solves the aboveproblems and embraces a novel class of compounds which has beendeveloped and which inhibit the human 11-β-hydroxysteroid dehydrogenasetype 1 enzyme (11-β-HSD₁), and may therefore be of use in the treatingdisorders such as diabetes, obesity, glaucoma, osteoporosis, cognitivedisorders, immune disorders, and hypertension.

[0033] One object of the present invention is a compound of formula (I)

[0034] wherein:

[0035] T is an aryl ring or heteroaryl ring, optionally independentlysubstituted by [R]_(n), wherein n is an integer 0-5, and R is hydrogen,aryl, heteroaryl, a heterocyclic ring, optionally halogenatedC₁₋₆-alkyl, optionally halogenated C₁₋₆-alkoxy, C₁₋₆-alkylsulfonyl,carboxy, cyano, nitro, halogen, amine which is mono- or di-substituted,amide which is optionally mono- or di-substituted, aryloxy,arylsulfonyl, arylamino, wherein aryl, heteroaryl and aryloxy residuesand heterocyclic rings can further be optionally substituted in one ormore positions independently of each other by C₁₋₆-acyl, C₁₋₆-alkylthio,cyano, nitro, hydrogen, halogen, optionally halogenated C₁₋₆-alkyl,optionally halogenated C₁₋₆-alkoxy, amide which is optionally mono- ordi-substituted, (benzoylamino)methyl, carboxy, 2-thienylmethylamino or({[4-(2-ethoxy-2-oxoethyl)-1,3-thiazol-2-yl]amino}carbonyl);

[0036] R¹ is hydrogen or C₁₋₆-alkyl;

[0037] A₁ and A₂ are a nitrogen atom or C-Z, provided that A₁ and A₂have different meanings, wherein:

[0038] Z is selected from an aryl ring or heteroaryl ring, which canfurther be optionally substituted in one or more positions independentlyof each other by hydrogen, C₁₋₆-alkyl, halogenated C₁₋₆-alkyl, halogen,C₁₋₆-alkoxy, nitro, C₁₋₆-alkoxycarbonyl, C₁₋₆-alkylsulfonyl, acetylaminoor aryloxy, wherein the aryloxy can further be optionally substituted inone or more positions independently of each other by hydrogen andhalogen; or is X—Y—R², wherein

[0039] X is CH₂ or CO;

[0040] Y is CH₂, CO or a single bond;

[0041] R² is selected from C₁₋₆-alkyl, azido, arylthio, heteroarylthio,halogen, hydroxymethyl, 2-hydroxyethylaminomethyl,methylsulfonyloxymethyl, 3-oxo-4-morpholinolinylmethylene,C₁₋₆-alkoxycarbonyl, 5-methyl-1,3,4-oxadiazol-2-yl;

[0042] NR³R⁴, wherein R³ and R⁴ are each independently selected fromhydrogen, C₁₋₆-alkyl, optionally halogenated C₁₋₆-alkylsulfonyl,C₁₋₆-alkoxy, 2-methoxyethyl, 2-hydroxyethyl, 1-methylimidazolylsulfonyl,C₁₋₆-acyl, cyclohexylmethyl, cyclopropanecarbonyl, aryl, optionallyhalogenated arylsulfonyl, furylcarbonyl, tetrahydro-2-furanylmethyl,N-carbethoxypiperidyl, or C₁₋₆-alkyl substituted with one or more aryl,heterocyclic or heteroaryl, or

[0043] NR³R⁴ represent together heterocyclic systems which can beimidazole, piperidine, pyrrolidine, piperazine, morpholine, oxazepine,oxazole, thiomorpholine, 1,1-dioxidothiomorpholine,2-(3,4-dihydro-2(1H)isoquinolinyl),(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl, which heterocyclic systemscan be optionally substituted by C₁₋₆-alkyl, C₁₋₆-acyl, hydroxy, oxo,t-butoxycarbonyl;

[0044] OCONR³R⁴, wherein R³ and R⁴ are each independently selected fromhydrogen, C₁₋₆-alkyl or form together with the N-atom to which they areattached morpholinyl;

[0045] R⁵O, wherein R⁵ is hydrogen, optionally halogenated C₁₋₆-alkyl,aryl, heteroaryl, C₁₋₆-acyl, C₁₋₆-alkylsulfonyl, arylcarbonyl,heteroarylcarbonyl, 2-carbomethoxyphenyl;

[0046] or a salt, hydrate or solvate thereof;

[0047] with the proviso that when:

[0048] A₁ is C-Z and A₂ is a nitrogen atom, then T is not phenyl onlysubstituted with a nitrogen containing substituent in position 4 with anitrogen atom closest to the phenyl ring, is not phenyl only substitutedwith methyl in position 2, is not phenyl only substituted with methyl inposition 4, and is not phenyl only substituted with ethyl in position 4;

[0049] A₁ is a nitrogen atom and A₂ is C-Z, then Z is not 2-furyl,5-nitro-2-furyl, 2-thienyl, optionally substituted phenyl,para-substituted benzyl;

[0050] A₁ is a nitrogen atom and A₂ is C-Z, X is CH₂, Y is a singlebond, then R² is not C₁₋₆-alkyl, methoxy, ethoxy, benzothiazol-2-ylthioand NR³R⁴, wherein R³ and R⁴ are selected from methyl, ethyl, n-propyl,n-butyl;

[0051] A₁ is a nitrogen atom and A₂ is C-Z, X is CH₂, Y is CH₂, then R²is not C₁₋₆-alkyl and NR³R⁴, wherein R³ and R⁴ are selected from methyl,ethyl, n-propyl, n-butyl.

[0052] It is preferred that:

[0053] T is selected from 5-chloro-1,3-dimethyl-1H-pyrazol-4-yl;4-chloro-2,3,1-benzoxadiazolyl; 5-(dimethylamino)-1-naphthyl;1-methylimidazol-4-yl; 1-naphthyl; 2-naphthyl; 8-quinolinyl;

[0054] thienyl substituted with one or more of (benzoylamino)methyl,bromo, chloro, 3-isoxazolyl, 2-(methylsulfanyl)-4-pyrimidinyl,1-methyl-5-(trifluoromethyl)pyrazol-3-yl, phenylsulfonyl, pyridyl;

[0055] phenyl substituted with one or more of acetylamino,3-acetylaminophenyl, 3-acetylphenyl, benzeneamino, 1,3-benzodioxol-5-yl,2-benzofuryl, benzylamino, 3,5-bis(trifluoromethyl)phenyl, bromo,butoxy, carboxy, chloro, 4-carboxyphenyl, 3-chloro-2-cyanophenoxy,4-chlorophenyl, 5-chloro-2-thienyl, cyano, 3,4-dichlorophenyl,({[4-(2-ethoxy-2-oxoethyl)-1,3-thiazol-2-yl]amino}carbonyl), fluoro,5-fluoro-2-methoxyphenyl, 2-furyl, hydrogen, iodo, isopropyl,methanesulfonyl, methoxy, methyl, 4-methyl-1-piperazinyl,4-methyl-1-piperidinyl, 4-methylsulfanylphenyl, 5-methyl-2-thienyl,4-morpholinyl, nitro, 3-nitrophenyl, phenoxy, phenyl, n-propyl,4-pyridyl, 3-pyridylmethylamino, 1-pyrrolidinyl, 2-thienyl, 3-thienyl,2-thienylmethylamino, trifluoromethoxy, 4-trifluoromethoxyphenyl,trifluoromethyl; or

[0056] R¹ is hydrogen or methyl;

[0057] A₁ and A₂ are a nitrogen atom or C-Z, provided that A₁ and A₂have different meanings, wherein:

[0058] Z is selected from 1-benzothien-3-yl, 3-(2,5-dimethylfuryl),pyridinyl; thienyl optionally substituted with one or more of chloro,methylsulfonyl; phenyl optionally substituted with one or more ofethoxycarbonyl, nitro, fluoro, methyl, methoxy, acetylamino, chloro,4-chlorophenoxy, trifluoromethyl; or is X—Y—R², wherein

[0059] X is CH₂ or CO;

[0060] Y is CH₂, CO or a single bond;

[0061] R² is selected from n-propyl, azido, bromo, chloro,2-pyridinylsulfanyl, 3-oxo-4-morpholinolinylmethylene, ethoxycarbonyl,5-methyl-1,3,4-oxadiazol-2-yl, hydroxymethyl, 2-hydroxyethylaminomethyl,methylsulfonyloxymethyl;

[0062] NR³R⁴, wherein R³ and R⁴ are each independently selected fromacetyl, benzhydryl, 1,3-benzodioxol-5-ylmethyl, benzyl,3-chloro-2-methylphenylsulfonyl, cyclohexyl, cyclohexylmethyl,cyclopropanecarbonyl, ethyl, 2-furylcarbonyl, 2-furylmethyl, hydrogen,2-hydroxyethyl, 2-(1H-indol-3-yl)ethyl, isopropyl, methoxy,2-methoxyethyl, methyl, 4-(1-methylimidazolyl)sulfonyl, methylsulfonyl,phenyl, (1S)-phenylethyl, n-propyl, tetrahydro-2-furanylmethyl,trifluoromethylsulfonyl, N-carbethoxypiperidyl; or

[0063] NR³R⁴ represent together 4-acetylpiperazinyl,4-t-butoxycarbonylpiperazinyl, 2-(3,4-dihydro-2(1H)isoquinolinyl),(2R,6S)-2,6-dimethylmorpholinyl, (2R)-2,4-dimethyl-1-piperazinyl,2-hydroxy-3-oxomorpholinyl, imidazolyl, 2-methyl-3-oxomorpholinyl,4-methyl-2-oxopiperazinyl, 4-methylpiperazinyl, morpholinyl,(1S,4S)-2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl, 2-oxoimidazolinyl,3-oxomorpholinyl, 3-oxo-1,4-oxazepinyl, 2-oxooxazolinyl, piperazinyl;piperidinyl; pyrrolidinyl; pyrrolidonyl, thiomorpholinyl;1,1-dioxido-thiomorpholinyl;

[0064] OCONR³R⁴, wherein R³ and R⁴ are each independently selected fromethyl, hydrogen or form together with the N-atom to which they areattached morpholinyl;

[0065] R⁵O, wherein R⁵ is acetyl, benzoyl, benzyl, ethyl, 2-fluoroethyl,2-furylcarbonyl, hydrogen, isobutyryl, isopropyl, methyl,2-carbomethoxyphenyl, methylsulfonyl, phenyl, n-propionyl, 3-pyridinyl,2,2,2-trifluoroethyl;

[0066] with the proviso that when:

[0067] A₁ is C-Z and A₂ is a nitrogen atom, then T is not phenyl onlysubstituted with nitro, 4-morpholinyl, 1-pyrrolidinyl, acetylamino,benzeneamino, benzylamino, 3-pyridylmethylamino, 4-methyl-1-piperazinyl,4-methyl-1-piperidinyl, or 2-thienylmethylamino in position 4, is notphenyl only substituted with methyl in position 2, and is not phenylonly substituted with methyl in position 4;

[0068] A₁ is a nitrogen atom and A₂ is C-Z, then Z is not 2-thienyl andphenyl optionally substituted with one or more of ethoxycarbonyl, nitro,fluoro, methyl, methoxy, acetylamino, chloro, 4-chlorophenoxy,trifluoromethyl;

[0069] A₁ is a nitrogen atom and A₂ is C-Z, X is CH₂, Y is a singlebond, then R² is not n-propyl, methoxy, ethoxy and NR³R⁴, wherein R³ andR⁴ are selected from methyl, ethyl, n-propyl;

[0070] A₁ is a nitrogen atom and A₂ is C-Z, X is CH₂, Y is CH₂, then R²is not n-propyl and NR³R⁴, wherein R³ and R⁴ are selected from methyl,ethyl, n-propyl.

[0071] When A₁ is C-Z and A₂ is a nitrogen atom, then it is preferredthat:

[0072] Z is selected from 1-benzothien-3-yl, 3-(2,5-dimethylfuryl),pyridinyl; thienyl optionally substituted with one or more of chloro,methylsulfonyl; phenyl optionally substituted with one or more ofethoxycarbonyl, nitro, fluoro, methyl, methoxy, acetylamino, chloro,4-chlorophenoxy, trifluoromethyl; or is X—Y—R², wherein

[0073] X is CH₂ or CO;

[0074] Y is CH₂, CO or a single bond;

[0075] R² is selected from n-propyl, azido, bromo, chloro,2-pyridinylsulfanyl, 3-oxo-4-morpholinolinylmethylene, ethoxycarbonyl,5-methyl-1,3,4-oxadiazol-2-yl, hydroxymethyl, 2-hydroxyethylaminomethyl,methylsulfonyloxymethyl;

[0076] NR³R⁴, wherein R³ and R⁴ are each independently selected fromacetyl, benzhydryl, 1,3-benzodioxol-5-ylmethyl, benzyl,3-chloro-2-methylphenylsulfonyl, cyclohexyl, cyclohexylmethyl,cyclopropanecarbonyl, ethyl, 2-furylcarbonyl, 2-furylmethyl, hydrogen,2-hydroxyethyl, 2-(1H-indol-3-yl)ethyl, isopropyl, methoxy,2-methoxyethyl, methyl, 4-(1-methylimidazolyl)sulfonyl, methylsulfonyl,phenyl, (1S)-phenylethyl, n-propyl, tetrahydro-2-furanylmethyl,trifluoromethylsulfonyl, N-carbethoxypiperidyl; or

[0077] NR³R⁴ represent together 4-acetylpiperazinyl,4-t-butoxycarbonylpiperazinyl, 2-(3,4-dihydro-2(1H)isoquinolinyl), (2R,6S)-2,6-dimethylmorpholinyl, (2R)-2,4-dimethyl-1-piperazinyl,2-hydroxy-3-oxomorpholinyl, imidazolyl, 2-methyl-3-oxomorpholinyl,4-methyl-2-oxopiperazinyl, 4-methylpiperazinyl, morpholinyl,(1S,4S)-2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl, 2-oxoimidazolinyl,3-oxomorpholinyl, 3-oxo-1,4-oxazepinyl, 2-oxooxazolinyl, piperazinyl;piperidinyl; pyrrolidinyl; pyrrolidonyl, thiomorpholinyl;1,1-dioxido-thiomorpholinyl;

[0078] OCONR³R⁴, wherein R³ and R⁴ are each independently selected fromethyl, hydrogen or form together with the N-atom to which they areattached morpholinyl;

[0079] R⁵O, wherein R⁵ is acetyl, benzoyl, benzyl, ethyl, 2-fluoroethyl,2-furylcarbonyl, hydrogen, isobutyryl, isopropyl, methyl,2-carbomethoxyphenyl, methylsulfonyl, phenyl, n-propionyl, 3-pyridinyl,2,2,2-trifluoroethyl,

[0080] then it is preferred that T is selected from5-chloro-1,3-dimethyl-1H-pyrazol-4-yl; 4-chloro-2,3,1-benzoxadiazolyl;5-(dimethylamino)-1-naphthyl; 1-methylimidazol-4-yl; 1-naphthyl;2-naphthyl; 8-quinolinyl;

[0081] thienyl substituted with one or more of (benzoylamino)methyl,bromo, chloro, 3-isoxazolyl, 2-(methylsulfanyl)-4-pyrimidinyl,1-methyl-5-(trifluoromethyl)pyrazol-3-yl, phenylsulfonyl, pyridyl;

[0082] phenyl, substituted with one or more of (i)-(iii):

[0083] (i) 3-acetylaminophenyl, 3-acetylphenyl, 1,3-benzodioxol-5-yl,2-benzofuryl, 3,5-bis(trifluoromethyl)phenyl, bromo, butoxy, carboxy,chloro, 4-carboxyphenyl, 3-chloro-2-cyanophenoxy, 4-chlorophenyl,5-chloro-2-thienyl, cyano, 3,4-dichlorophenyl,({[4-(2-ethoxy-2-oxoethyl)-1,3-thiazol-2-yl]amino}carbonyl), fluoro,5-fluoro-2-methoxyphenyl, 2-furyl, hydrogen, iodo, isopropyl,methanesulfonyl, methoxy, 4-methylsulfanylphenyl, 5-methyl-2-thienyl,3-nitrophenyl, phenoxy, phenyl, n-propyl, 4-p yridyl, 2-thienyl,3-thienyl, trifluoromethoxy, 4-trifluoromethoxyphenyl, trifluoromethyl;and, furthermore, optionally with at least one substituent selected fromacetylamino, 3-acetylaminophenyl, 3-acetylphenyl, benzeneamino,1,3-benzodioxol-5-yl, 2-benzofuryl, benzylamino,3,5-bis(trifluoromethyl)phenyl, bromo, butoxy, carboxy, chloro,4-carboxyphenyl, 3-chloro-2-cyanophenoxy, 4-chlorophenyl,5-chloro-2-thienyl, cyano, 3,4-dichlorophenyl,({[4-(2-ethoxy-2-oxoethyl)-1,3-thiazol-2-yl]amino}carbonyl), fluoro,5-fluoro-2-methoxyphenyl, 2-furyl, hydrogen, iodo, isopropyl,methanesulfonyl, methoxy, methyl, 4-methyl-1-piperazinyl,4-methyl-1-piperidinyl, 4-methylsulfanylphenyl, 5-methyl-2-thienyl,4-morpholinyl, nitro, 3-nitrophenyl, phenoxy, phenyl, n-propyl,4-pyridyl, 3-pyridylmethylamino, 1-pyrrolidinyl, 2-thienyl, 3-thienyl,2-thienylmethylamino, trifluoromethoxy, 4-trifluoromethoxyphenyl,trifluoromethyl;

[0084] (ii) nitro, 4-morpholinyl, 1-pyrrolidinyl, acetylamino,benzeneamino, benzylamino, 3-pyridylmethylamino, 4-methyl-1-piperazinyl,4-methyl-1-piperidinyl, or 2-thienylmethylamino in one or more ofpositions 2 and 3; and, furthermore, optionally with at least onesubstituent selected from acetylamino, 3-acetylaminophenyl,3-acetylphenyl, benzeneamino, 1,3-benzodioxol-5-yl, 2-benzofuryl,benzylamino, 3,5-bis(trifluoromethyl)phenyl, bromo, butoxy, carboxy,chloro, 4-carboxyphenyl, 3-chloro-2-cyanophenoxy, 4-chlorophenyl,5-chloro-2-thienyl, cyano, 3,4-dichlorophenyl,({[4-(2-ethoxy-2-oxoethyl)-1,3-thiazol-2-yl]amino}carbonyl), fluoro,5-fluoro-2-methoxyphenyl, 2-furyl, hydrogen, iodo, isopropyl,methanesulfonyl, methoxy, methyl, 4-methyl-1-piperazinyl,4-methyl-1-piperidinyl, 4-methylsulfanylphenyl, 5-methyl-2-thienyl,4-morpholinyl, nitro, 3-nitrophenyl, phenoxy, phenyl, n-propyl,4-pyridyl, 3-pyridylmethylamino, 1-pyrrolidinyl, 2-thienyl, 3-thienyl,2-thienylmethylamino, trifluoromethoxy, 4-trifluoromethoxyphenyl,trifluoromethyl;

[0085] (iii) methyl in position 3; and, furthermore, optionally with atleast one substituent selected from acetylamino, 3-acetylaminophenyl,3-acetylphenyl, benzeneamino, 1,3-benzodioxol-5-yl, 2-benzofuryl,benzylamino, 3,5-bis(trifluoromethyl)phenyl, bromo, butoxy, carboxy,chloro, 4-carboxyphenyl, 3-chloro-2-cyanophenoxy, 4-chlorophenyl,5-chloro-2-thienyl, cyano, 3,4-dichlorophenyl,({[4-(2-ethoxy-2-oxoethyl)-1,3-thiazol-2-yl]amino}carbonyl), fluoro,5-fluoro-2-methoxyphenyl, 2-furyl, hydrogen, iodo, isopropyl,methanesulfonyl, methoxy, methyl, 4-methyl-1-piperazinyl,4-methyl-1-piperidinyl, 4-methylsulfanylphenyl, 5-methyl-2-thienyl,4-morpholinyl, nitro, 3-nitrophenyl, phenoxy, phenyl, n-propyl,4-pyridyl, 3-pyridylmethylamino, 1-pyrrolidinyl, 2-thienyl, 3-thienyl,2-thienylmethylamino, trifluoromethoxy, 4-trifluoromethoxyphenyl,trifluoromethyl;

[0086] When A₁ is a nitrogen atom and A₂ is C-Z, then it is preferredthat:

[0087] Z is selected from 1-benzothien-3-yl, 3-(2,5-dimethylfuryl),pyridinyl; thienyl substituted with one or more of chloro,methylsulfonyl; or is X—Y—R², wherein

[0088] X is CH₂ or CO;

[0089] Y is CH₂, CO or a single bond;

[0090] R² is selected from n-propyl, azido, bromo, chloro,2-pyridinylsulfanyl, 3-oxo-4-morpholinolinylmethylene, ethoxycarbonyl,5-methyl-1,3,4-oxadiazol-2-yl, hydroxymethyl, 2-hydroxyethylaminomethyl,methylsulfonyloxymethyl;

[0091] NR³R⁴, wherein R³ and R⁴ are each independently selected fromacetyl, benzhydryl, 1,3-benzodioxol-5-ylmethyl, benzyl,3-chloro-2-methylphenylsulfonyl, cyclohexyl, cyclohexylmethyl,cyclopropanecarbonyl, ethyl, 2-furylcarbonyl, 2-furylmethyl, hydrogen,2-hydroxyethyl, 2-(1H-indol-3-yl)ethyl, isopropyl, methoxy,2-methoxyethyl, methyl, 4-(1-methylimidazolyl)sulfonyl, methylsulfonyl,phenyl, (1S)-phenylethyl, n-propyl, tetrahydro-2-furanylmethyl,trifluoromethylsulfonyl, N-carbethoxypiperidyl; or

[0092] NR³R⁴ represent together 4-acetylpiperazinyl,4-t-butoxycarbonylpiperazinyl, 2-(3,4-dihydro-2(1 H)isoquinolinyl),(2R,6S)-2,6-dimethylmorpholinyl, (2R)-2,4-dimethyl-1-piperazinyl,2-hydroxy-3-oxomorpholinyl, imidazolyl, 2-methyl-3-oxomorpholinyl,4-methyl-2-oxopiperazinyl, 4-methylpiperazinyl, morpholinyl,(1S,4S)-2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl, 2-oxoimidazolinyl,3-oxomorpholinyl, 3-oxo-1,4-oxazepinyl, 2-oxooxazolinyl, piperazinyl;piperidinyl; pyrrolidinyl; pyrrolidonyl, thiomorpholinyl;1,1-dioxido-thiomorpholinyl;

[0093] OCONR³R⁴, wherein R³ and R⁴ are each independently selected fromethyl, hydrogen or form together with the N-atom to which they areattached morpholinyl;

[0094] R⁵O, wherein R⁵ is acetyl, benzoyl, benzyl, ethyl, 2-fluoroethyl,2-furylcarbonyl, hydrogen, isobutyryl, isopropyl, methyl,2-carbomethoxyphenyl, methylsulfonyl, phenyl, n-propionyl, 3-pyridinyl,2,2,2-trifluoroethyl;

[0095] When A₁ is a nitrogen and A₂ is C-Z, i e C—X—Y—R , wherein X isCH₂ and Y is a single bond, then it is preferred that R² is selectedfrom azido, bromo, chloro, 2-pyridinylsulfanyl,3-oxo-4-morpholinolinylmethylene, ethoxycarbonyl,5-methyl-1,3,4-oxadiazol-2-yl, hydroxymethyl, 2-hydroxyethylaminomethyl,methylsulfonyloxymethyl;

[0096] NR³R⁴, wherein R³ and R⁴ are each independently selected fromacetyl, benzhydryl, 1,3-benzodioxol-5-ylmethyl, benzyl,3-chloro-2-methylphenylsulfonyl, cyclohexyl, cyclohexylmethyl,cyclopropanecarbonyl, 2-furylcarbonyl, 2-furylmethyl, hydrogen,2-hydroxyethyl, 2-(1H-indol-3-yl)ethyl, isopropyl, methoxy,2-methoxyethyl, 4-(1-methylimidazolyl)sulfonyl, methylsulfonyl, phenyl,(1S)-phenylethyl, tetrahydro-2-furanylmethyl, trifluoromethylsulfonyl,N-carbethoxypiperidyl; or

[0097] NR³R⁴ represent together 4-acetylpiperazinyl,4-t-butoxycarbonylpiperazinyl, 2-(3,4-dihydro-2(1H)isoquinolinyl),(2R,6S)-2,6-dimethylmorpholinyl, (2R)-2,4-dimethyl-1-piperazinyl,2-hydroxy-3-oxomorpholinyl, imidazolyl, 2-methyl-3-oxomorpholinyl,4-methyl-2-oxopiperazinyl, 4-methylpiperazinyl, morpholinyl,(1S,4S)-2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl, 2-oxoimidazolinyl,3-oxomorpholinyl, 3-oxo-1,4-oxazepinyl, 2-oxooxazolinyl, piperazinyl;piperidinyl; pyrrolidinyl; pyrrolidonyl, thiomorpholinyl;1,1-dioxido-thiomorpholinyl;

[0098] OCONR³R⁴, wherein R³ and R⁴ are each independently selected fromethyl, hydrogen or form together with the N-atom to which they areattached morpholinyl;

[0099] R⁵O, wherein R⁵ is acetyl, benzoyl, benzyl, 2-fluoroethyl,2-furylcarbonyl, hydrogen, isobutyryl, isopropyl, 2-carbomethoxyphenyl,methylsulfonyl, phenyl, n-propionyl, 3-pyridinyl, 2,2,2-trifluoroethyl.

[0100] When A₁ is a nitrogen and A₂ is C-Z, i e C—X—Y—R², wherein X isCH₂ and Y is CH₂, then it is preferred that R² is selected from azido,bromo, chloro, 2-pyridinylsulfanyl, 3-oxo-4-morpholinolinylmethylene,ethoxycarbonyl, 5-methyl-1,3,4-oxadiazol-2-yl, hydroxymethyl,2-hydroxyethylaminomethyl, methylsulfonyloxymethyl;

[0101] NR³R⁴, wherein R³ and R⁴ are each independently selected fromacetyl, benzhydryl, 1,3-benzodioxol-5-ylmethyl, benzyl,3-chloro-2-methylphenylsulfonyl, cyclohexyl, cyclohexylmethyl,cyclopropanecarbonyl, 2-furylcarbonyl, 2-furylmethyl, hydrogen,2-hydroxyethyl, 2-(1H-indol-3-yl)ethyl, isopropyl, methoxy,2-methoxyethyl, 4-(1-methylimidazolyl)sulfonyl, methylsulfonyl, phenyl,(1S)-phenylethyl, tetrahydro-2-furanylmethyl, trifluoromethylsulfonyl,N-carbethoxypiperidyl; or

[0102] NR³R⁴ represent together 4-acetylpiperazinyl,4-t-butoxycarbonylpiperazinyl, 2-(3,4-dihydro-2(1H)isoquinolinyl),(2R,6S)-2,6-dimethylmorpholinyl, (2R)-2,4-dimethyl-1-piperazinyl,2-hydroxy-3-oxomorpholinyl, imidazolyl, 2-methyl-3-oxomorpholinyl,4-methyl-2-oxopiperazinyl, 4-methylpiperazinyl, morpholinyl,(1S,4S)-2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl, 2-oxoimidazolinyl,3-oxomorpholinyl, 3-oxo-1,4-oxazepinyl, 2-oxooxazolinyl, piperazinyl;piperidinyl; pyrrolidinyl; pyrrolidonyl, thiomorpholinyl;1,1-dioxido-thiomorpholinyl;

[0103] OCONR³R⁴, wherein R³ and R⁴ are each independently selected fromethyl, hydrogen or form together with the N-atom to which they areattached morpholinyl;

[0104] R⁵O, wherein R⁵ is acetyl, benzoyl, benzyl, ethyl, 2-fluoroethyl,2-furylcarbonyl, hydrogen, isobutyryl, isopropyl, methyl,2-carbomethoxyphenyl, methylsulfonyl, phenyl, n-propionyl, 3-pyridinyl,2,2,2-trifluoroethyl.

[0105] The following list shows particularly preferred compounds. Theyare divided into the following categories:

[0106]ethyl(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)acetate

[0107](5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)aceticacid

[0108]2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)-N-methylacetamide

[0109]2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]aamino}-1,3,4-thiadiazol-2-yl)-N-ethylacetamide

[0110]2,5-dichloro-N-[5-(3-chlorothien-2-yl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide

[0111] isopropyl (5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)acetate

[0112]3-chloro-N-[5-(2-hydroxyethyl)-1,3,4-thiadiazol-2-yl]-2-methylbenzenesulfonamide

[0113]3-chloro-N-[5-(2-ethoxyethyl)-1,3,4-thiadiazol-2-yl]-2-methylbenzenesulfonamide

[0114]2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)-N,N-diethylacetamide

[0115]methyl(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)acetate

[0116]3-chloro-N-[5-(2-isopropoxyethyl)-1,3,4-thiadiazol-2-yl]-2-methylbenzenesulfonamide

[0117]3-chloro-N-[5-(2-methoxyethyl)-1,3,4-thiadiazol-2-yl]-2-methylbenzenesulfonamide

[0118]2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)ethylmethanesulfonate

[0119]2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)acetamide

[0120]3-chloro-N-{5-[2-(2-fluoroethoxy)ethyl]-1,3,4-thiadiazol-2-yl}-2-methylbenzenesulfonamide

[0121]3-chloro-2-methyl-N-{5-[2-(2,2,2-trifluoroethoxy)ethyl]-1,3,4-thiadiazol-2-yl}benzenesulfonamide

[0122]2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)ethylacetate

[0123]3-chloro-2-methyl-N-[5-(2-morpholin-4-ylethyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide

[0124]N-[5-(2-bromoethyl)-1,3,4-thiadiazol-2-yl]-3-chloro-2-methylbenzenesulfonamide

[0125]2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)ethylmorpholine-4-carboxylate

[0126]2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)ethyldiethylcarbamate

[0127]2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)ethylpropionate

[0128] 2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)ethyl 2-methylpropanoate

[0129]2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)ethyl2-furoate

[0130] 2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)ethyl benzoate

[0131]2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)-N-methoxy-N-methylacetamide

[0132] 2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)ethyl ethylcarbamate

[0133]N-[2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)ethyl]-N-ethylacetamide

[0134]3-chloro-2-methyl-N-[5-(2-oxopentyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide

[0135]N-{5-[2-(1,1-dioxidothiomorpholin-4-yl)-2-oxoethyl]-1,3,4-thiadiazol-2-yl}-4-propylbenzenesulfonamide

[0136]2,4,6-trichloro-N-[5-(2-morpholin-4-ylethyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide

[0137]2,4-dichloro-N-[5-(2-morpholin-4-ylethyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide

[0138]3-chloro-2-methyl-N-{5-[2-(3-oxomorpholin-4-yl)ethyl]-1,3,4-thiadiazol-2-yl}benzenesulfonamide

[0139]2,4-dichloro-6-methyl-N-[5-(2-morpholin-4-ylethyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide

[0140]N-[5-(2-morpholin-4-ylethyl)-1,3,4-thiadiazol-2-yl]-4-propylbenzenesulfonamide

[0141]2,4-dichloro-6-methyl-N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide

[0142]2,4,6-trichloro-N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide

[0143]N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2-yl]-1,1′-biphenyl-4-sulfonamide

[0144]N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2-yl]-4-propylbenzenesulfonamide

[0145]N-[5-(2-oxo-2-thiomorpholin-4-ylethyl)-1,3,4-thiadiazol-2-yl]-1,1′-biphenyl-4-sulfonamide

[0146]N-[5-(2-oxo-2-thiomorpholin-4-ylethyl)-1,3,4-thiadiazol-2-yl]-4-propylbenzenesulfonamide

[0147]2,4-dichloro-6-methyl-N-[5-(2-oxo-2-thiomorpholin-4-ylethyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide

[0148]N-[5-(2-oxo-2-piperidin-1-ylethyl)-1,3,4-thiadiazol-2-yl]-1,1′-biphenyl-4-sulfonamide

[0149]N-[5-(2-oxo-2-piperidin-1-ylethyl)-1,3,4-thiadiazol-2-yl]-4-propylbenzenesulfonamide

[0150]2,4-dichloro-6-methyl-N-[5-(2-oxo-2-piperidin-1-ylethyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide

[0151]2,4,6-trichloro-N-[5-(2-oxo-2-piperidin-1-ylethyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide

[0152]ethyl(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)(oxo)acetate

[0153]2-{5-[(1,1′-biphenyl-4-ylsulfonyl)amino]-1,3,4-thiadiazol-2-yl}-N-ethyl-N-methylacetamide

[0154]N-ethyl-N-methyl-2-(5-{[(4-propylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)acetamide

[0155]2-(5-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)-N-ethyl-N-methylacetamide

[0156]N-ethyl-N-methyl-2-(5-{[(2,4,6-trichlorophenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)acetamide

[0157]2,4,6-trichloro-N-[5-(2-oxo-2-thiomorpholin-4-ylethyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide

[0158]2-{5-[(1,1′-biphenyl-4-ylsulfonyl)amino]-1,3,4-thiadiazol-2-yl}-N-isopropyl-N-methylacetamide

[0159]2-{5-[(1,1′-biphenyl-4-ylsulfonyl)amino]-1,3,4-thiadiazol-2-yl}-N,N-diethylacetamide

[0160]N,N-diethyl-2-(5-{[(4-propylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)acetamide

[0161]2-(5-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)-N,N-diethylacetamide

[0162]N,N-diethyl-2-(5-{[(2,4,6-trichlorophenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)acetamide

[0163]2-{5-[(1,1′-biphenyl-4-ylsulfonyl)amino]-1,3,4-thiadiazol-2-yl}-N,N-diisopropylacetamide

[0164]N,N-diisopropyl-2-(5-{[(4-propylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)acetamide

[0165]2-(5-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)-N,N-diisopropylacetamide

[0166]N,N-diisopropyl-2-(5-{[(2,4,6-trichlorophenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)acetamide

[0167]4-propyl-N-(5-pyridin-3-yl-1,3,4-thiadiazol-2-yl)benzenesulfonamide

[0168]3-chloro-N-[5-(5-chlorothien-2-yl)-1,3,4-thiadiazol-2-yl]-2-methylbenzenesulfonamide

[0169]2,4,6-trichloro-N-(5-pyridin-3-yl-1,3,4-thiadiazol-2-yl)benzenesulfonamide

[0170]2,4,6-trichloro-N-[5-(5-chlorothien-2-yl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide

[0171]N-(5-pyridin-3-yl-1,3,4-thiadiazol-2-yl)-1,1′-biphenyl-4-sulfonamide

[0172]2,4-dichloro-6-methyl-N-(5-pyridin-3-yl-1,3,4-thiadiazol-2-yl)benzenesulfonamide

[0173]2,4-dichloro-N-[5-(5-chlorothien-2-yl)-1,3,4-thiadiazol-2-yl]-6-methylbenzenesulfonamide

[0174]2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)-N,N-dipropylacetamide

[0175]3-chloro-2-methyl-N-[5-(2-oxo-2-piperazin-1-ylethyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide

[0176]2,4-dichloro-N-[5-(2,5-dimethyl-3-furyl)-1,3,4-thiadiazol-2-yl]-6-methylbenzenesulfonamide

[0177]N-[5-(3-chlorothien-2-yl)-1,3,4-thiadiazol-2-yl]-4-propylbenzenesulfonamide

[0178]3-chloro-N-[5-(3-chlorothien-2-yl)-1,3,4-thiadiazol-2-yl]-2-methylbenzenesulfonamide

[0179]2,4,6-trichloro-N-[5-(3-chlorothien-2-yl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide

[0180]2,4-dichloro-N-[5-(3-chlorothien-2-yl)-1,3,4-thiadiazol-2-yl]-6-methylbenzenesulfonamide

[0181]4-bromo-2-methyl-N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide

[0182]N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2-yl]-2,4-bis(trifluoromethyl)benzenesulfonamide

[0183]2-methyl-N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2-yl]-4-(trifluoromethoxy)benzenesulfonamide

[0184]N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2-yl]-4-phenoxybenzenesulfonamide

[0185]4-chloro-2,6-dimethyl-N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide

[0186]2,4-dichloro-N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide

[0187] tert-butyl4-[(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)acetyl]piperazine-1-carboxylate

[0188]2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)-N,N-dimethylacetamide

[0189]3-chloro-2-methyl-N-{5-[2-(pyridin-3-yloxy)ethyl]-1,3,4-thiadiazol-2-yl}benzenesulfonamide

[0190]2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)-N-isopropyl-N-methylacetamide

[0191]2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)-N-ethyl-N-methylacetamide

[0192]3-chloro-2-methyl-N-[5-(2-oxo-2-thiomorpholin-4-ylethyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide

[0193]3-chloro-2-methyl-N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide

[0194]2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)-N,N-diisopropylacetamide

[0195]3-chloro-2-methyl-N-[5-(2-oxo-2-pyrrolidin-1-ylethyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide

[0196]3-chloro-2-methyl-N-[5-(2-oxo-2-piperidin-1-ylethyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide

[0197]3-chloro-2-methyl-N-[5-(morpholin-4-ylmethyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide

[0198] 3-chloro-N-{5-[2-( 1H-imidazol-1-yl)ethyl]-1,3,4-thiadiazol-2-yl}-2-methylbenzenesulfonamide

[0199]2,4,5-trichloro-N-[5-(3-chlorothien-2-yl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide

[0200]2,3,4-trichloro-N-[5-(3-chlorothien-2-yl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide

[0201]4-bromo-N-[5-(3-chlorothien-2-yl)-1,3,4-thiadiazol-2-yl]-2,5-difluorobenzenesulfonamide

[0202]4-bromo-5-chloro-N-[5-(3-chlorothien-2-yl)-1,3,4-thiadiazol-2-yl]thiophene-2-sulfonamide

[0203]2,6-dichloro-N-[5-(3-chlorothien-2-yl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide

[0204]N-[2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)ethyl]acetamide

[0205] 3-chloro-2-methyl-N-(5-{2(methylsulfonyl)amino]ethyl}-1,3,4-thiadiazol-2-yl)benzenesulfonamide

[0206]3-chloro-2-methyl-N-{5-[2-(3-oxo-1,4-oxazepan-4-yl)ethyl]-1,3,4-thiadiazol-2-yl}benzenesulfonamide

[0207] 3-chloro-2-methyl-N-{5-[2-(2-oxopyrrolidin-1-yl)ethyl]-1,3,4-thiadiazol-2-yl}benzenesulfonamide

[0208]3-chloro-2-methyl-N-(5-{2-[methyl(methylsulfonyl)amino]ethyl}-1,3,4-thiadiazol-2-yl)benzenesulfonamide

[0209]N-[2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)ethyl]-methylcyclopropanecarboxamide

[0210] 3-chloro-2-methyl-N-{5-[2-(4-methyl-2-oxopiperazin-1-yl)ethyl]-1,3,4-thiadiazol-2-yl}benzenesulfonamide

[0211]3-chloro-2-methyl-N-[5-(2-{[(trifluoromethyl)sulfonyl]amino}ethyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide

[0212]2,4-dichloro-N-{5-[2-(3-oxomorpholin-4-yl)ethyl]-1,3,4-thiadiazol-2-yl}benzenesulfonamide

[0213]2,4-dichloro-6-methyl-N-{5-[2-(3-oxomorpholin-4-yl)ethyl]-1,3,4-thiadiazol-2-yl}benzenesulfonamide

[0214]2,4,6-trichloro-N-{5-[2-(3-oxomorpholin-4-yl)ethyl]-1,3,4-thiadiazol-2-yl}benzenesulfonamide

[0215]4-(2-furyl)-N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide

[0216]5′-fluoro-2′-methoxy-N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2-yl]-1,1′-biphenyl-4-sulfonamide

[0217]4-(5-methylthien-2-yl)-N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide

[0218]3′-acetyl-N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2-yl]-1,1′-biphenyl-4-sulfonamide

[0219]N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2-yl]-4′-(trifluoromethoxy)-1,1′-biphenyl-4-sulfonamide

[0220]3′,4′-dichloro-N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2-yl]-1,1′-biphenyl-4-sulfonamide

[0221]4-(1,3-benzodioxol-5-yl)-N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide

[0222]4-(5-chlorothien-2-yl)-N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide

[0223]N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2-yl]-4-pyridin-4-ylbenzenesulfonamide

[0224]N-[4′-({[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2-yl]amino}sulfonyl)-1,1′-biphenyl-3-yl]acetamide

[0225]N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2-yl]-4-thien-3-ylbenzenesulfonamide

[0226]N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2-yl]-4-thien-2-ylbenzenesulfonamide

[0227]4′-(methylthio)-N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2-yl]-1,1′-biphenyl-4-sulfonamide

[0228]N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2-yl]-3′,5′-bis(trifluoromethyl)-1,1′-biphenyl-4-sulfonamide

[0229]4′-chloro-N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2-yl]-1,1′-biphenyl-4-sulfonamide

[0230]N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2-yl]-3′-nitro-1,1′-biphenyl-4-sulfonamide

[0231]3-chloro-2-methyl-N-[5-(2-{methyl[(trifluoromethyl)sulfonyl]amino}ethyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide

[0232]N-[2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)ethyl]-1-methyl-1H-imidazole-4-sulfonamide

[0233]3-chloro-N-{5-[2-(2-hydroxy-3-oxomorpholin-4-yl)ethyl]-1,3,4-thiadiazol-2-yl}-2-methylbenzenesulfonamide

[0234]4,5-dichloro-N-{5-[2-(3-oxomorpholin-4-yl)ethyl]-1,3,4-thiadiazol-2-yl}thiophene-2-sulfonamide

[0235]N-{5-[2-(3-oxomorpholin-4-yl)ethyl]-1,3,4-thiadiazol-2-yl}-4-phenoxybenzenesulfonamide

[0236]3-fluoro-N-{5-[2-(3-oxomorpholin-4-yl)ethyl]-1,3,4-thiadiazol-2-yl}benzenesulfonamide

[0237]N-{5-[2-(3-oxomorpholin-4-yl)ethyl]-1,3,4-thiadiazol-2-yl}-5-pyridin-2-ylthiophene-2-sulfonamide

[0238]N-{2-chloro-4-[({5-[2-(3-oxomorpholin-4-yl)ethyl]-1,3,4-thiadiazol-2-yl}amino)sulfonyl]phenyl}acetamide

[0239]ethyl(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)acetate

[0240](5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)aceticacid

[0241]2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)-N-methylacetamide

[0242]2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)-N-ethylacetamide

[0243]2,5-dichloro-N-[3-(3-chlorothien-2-yl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide

[0244] isopropyl(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)acetate

[0245]3-chloro-N-[3-(2-hydroxyethyl)-1,2,4-thiadiazol-5-yl]-2-methylbenzenesulfonamide

[0246]3-chloro-N-[3-(2-ethoxyethyl)-1,2,4-thiadiazol-5-yl]-2-methylbenzenesulfonamide

[0247]2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)-N,N-diethylacetamide

[0248]methyl(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)acetate

[0249]3-chloro-N-[3-(2-isopropoxyethyl)-1,2,4-thiadiazol-5-yl]-2-methylbenzenesulfonamide

[0250]3-chloro-N-[3-(2-methoxyethyl)-1,2,4-thiadiazol-5-yl]-2-methylbenzenesulfonamide

[0251]2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)ethylmethanesulfonate

[0252]2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)acetamide

[0253]3-chloro-N-{3-[2-(2-fluoroethoxy)ethyl]-1,2,4-thiadiazol-5-yl}-2-methylbenzenesulfonamide

[0254]3-chloro-2-methyl-N-{3-[2-(2,2,2-trifluoroethoxy)ethyl]-1,2,4-thiadiazol-5-yl}benzenesulfonamide

[0255]2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)ethylacetate

[0256]3-chloro-2-methyl-N-[3-(2-morpholin-4-ylethyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide

[0257]N-[3-(2-bromoethyl)-1,2,4-thiadiazol-5-yl]-3-chloro-2-methylbenzenesulfonamide

[0258]2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)ethylmorpholine-4-carboxylate

[0259]2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)ethyldiethylcarbamate

[0260]2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)ethylpropionate

[0261]2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)ethyl2-methylpropanoate

[0262]2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)ethyl2-furoate

[0263]2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)ethylbenzoate

[0264]2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)-N-methoxy-N-methylacetamide

[0265]3-chloro-N-{3-[2-(diethylamino)ethyl]-1,2,4-thiadiazol-5-yl}-2-methylbenzenesulfonamide

[0266]2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)ethylethylcarbamate

[0267]N-[2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)ethyl]-N-ethylacetamide

[0268]3-chloro-2-methyl-N-[3-(2-oxopentyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide

[0269]N-{3-[2-(1,1-dioxidothiomorpholin-4-yl)-2-oxoethyl]-1,2,4-thiadiazol-5-yl}-4-propylbenzenesulfonamide

[0270]2,4,6-trichloro-N-[3-(2-morpholin-4-ylethyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide

[0271]2,4-dichloro-N-[3-(2-morpholin-4-ylethyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide

[0272]3-chloro-2-methyl-N-{3-[2-(3-oxomorpholin-4-yl)ethyl]-1,2,4-thiadiazol-5-yl}benzenesulfonamide

[0273]2,4-dichloro-6-methyl-N-[3-(2-morpholin-4-ylethyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide

[0274]N-[3-(2-morpholin-4-ylethyl)-1,2,4-thiadiazol-5-yl]-4-propylbenzenesulfonamide

[0275]2,4-dichloro-6-methyl-N-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide

[0276]2,4,6-trichloro-N-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide

[0277]N-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5-yl]-1,1′-biphenyl-4-sulfonamide

[0278]N-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5-yl]-4-propylbenzenesulfonamide

[0279]N-[3-(2-oxo-2-thiomorpholin-4-ylethyl)-1,2,4-thiadiazol-5-yl]-1,1′-biphenyl-4-sulfonamide

[0280]N-[3-(2-oxo-2-thiomorpholin-4-ylethyl)-1,2,4-thiadiazol-5-yl]-4-propylbenzenesulfonamide

[0281]2,4-dichloro-6-methyl-N-[3-(2-oxo-2-thiomorpholin-4-ylethyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide

[0282]N-[3-(2-oxo-2-piperidin-1-ylethyl)-1,2,4-thiadiazol-5-yl]-1,1′-biphenyl-4-sulfonamide

[0283]N-[3-(2-oxo-2-piperidin-1-ylethyl)-1,2,4-thiadiazol-5-yl]-4-propylbenzenesulfonamide

[0284]2,4-dichloro-6-methyl-N-[3-(2-oxo-2-piperidin-1-ylethyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide

[0285]2,4,6-trichloro-N-[3-(2-oxo-2-piperidin-1-ylethyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide

[0286] N-(3-phenyl-1,2,4-thiadiazol-5-yl)-4-propylbenzenesulfonamide

[0287]ethyl(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)(oxo)acetate

[0288]3-chloro-2-methyl-N-(3-phenyl-1,2,4-thiadiazol-5-yl)benzenesulfonamide

[0289]3-chloro-N-[3-(4-fluoro-3-methylphenyl)-1,2,4-thiadiazol-5-yl]-2-methylbenzenesulfonamide

[0290]2,4,6-trichloro-N-(3-phenyl-1,2,4-thiadiazol-5-yl)benzenesulfonamide

[0291] N-(3-phenyl-1,2,4-thiadiazol-5-yl)-1,1′-biphenyl-4-sulfonamide

[0292]2,4-dichloro-6-methyl-N-(3-phenyl-1,2,4-thiadiazol-5-yl)benzenesulfonamide

[0293]2-{5-[(1,1′-biphenyl-4-ylsulfonyl)amino]-1,2,4-thiadiazol-3-yl}-N-ethyl-N-methylacetamide

[0294]N-ethyl-N-methyl-2-(5-{[(4-propylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)acetamide

[0295]2-(5-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)-N-ethyl-N-methylacetamide

[0296]N-ethyl-N-methyl-2-(5-{[(2,4,6-trichlorophenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)acetamide

[0297]2,4,6-trichloro-N-[3-(2-oxo-2-thiomorpholin-4-ylethyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide

[0298]2-{5-[(1,1′-biphenyl-4-ylsulfonyl)amino]-1,2,4-thiadiazol-3-yl}-N-isopropyl-N-methylacetamide

[0299]2-{5-[(1,1′-biphenyl-4-ylsulfonyl)amino]-1,2,4-thiadiazol-3-yl}-N,N-diethylacetamide

[0300]N,N-diethyl-2-(5-{[(4-propylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)acetamide

[0301]2-(5-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)-N,N-diethylacetamide

[0302]N,N-diethyl-2-(5-{[(2,4,6-trichlorophenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)acetamide

[0303]2-{5-[(1,1′-biphenyl-4-ylsulfonyl)amino]-1,2,4-thiadiazol-3-yl}-N,N-diisopropylacetamide

[0304]N,N-diisopropyl-2-(5-{[(4-propylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)acetamide

[0305]2-(5-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)-N,N-diisopropylacetamide

[0306]N,N-diisopropyl-2-(5-{[(2,4,6-trichlorophenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)acetamide

[0307]N-[4-(5-{[(4-propylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)phenyl]acetamide

[0308]4-propyl-N-(3-pyridin-3-yl-1,2,4-thiadiazol-5-yl)benzenesulfonamide

[0309]N-[3-(2-chloro-5-nitrophenyl)-1,2,4-thiadiazol-5-yl]-4-propylbenzenesulfonamide

[0310]N-[3-(2-chlorophenyl)-1,2,4-thiadiazol-5-yl]-4-propylbenzenesulfonamide

[0311]3-chloro-N-[3-(2-chloro-5-nitrophenyl)-1,2,4-thiadiazol-5-yl]-2-methylbenzenesulfonamide

[0312]3-chloro-N-[3-(5-chlorothien-2-yl)-1,2,4-thiadiazol-5-yl]-2-methylbenzenesulfonamide

[0313]3-chloro-N-[3-(2-chlorophenyl)-1,2,4-thiadiazol-5-yl]-2-methylbenzenesulfonamide

[0314]N-[4-(5-{[(2,4,6-trichlorophenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)phenyl]acetamide

[0315]2,4,6-trichloro-N-(3-pyridin-3-yl-1,2,4-thiadiazol-5-yl)benzenesulfonamide

[0316]2,4,6-trichloro-N-[3-(2-chloro-5-nitrophenyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide

[0317]2,4,6-trichloro-N-[3-(5-chlorothien-2-yl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide

[0318]2,4,6-trichloro-N-[3-(2-chlorophenyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide

[0319]N-(4-{5-[(1,1′-biphenyl-4-ylsulfonyl)amino]-1,2,4-thiadiazol-3-yl}phenyl)acetamide

[0320]N-(3-pyridin-3-yl-1,2,4-thiadiazol-5-yl)-1,1′-biphenyl-4-sulfonamide

[0321]N-[3-(2-chloro-5-nitrophenyl)-1,2,4-thiadiazol-5-yl]-1,1′-biphenyl-4-sulfonamide

[0322]N-[3-(2-chlorophenyl)-1,2,4-thiadiazol-5-yl]-1,1′-biphenyl-4-sulfonamide

[0323]N-[4-(5-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)phenyl]acetamide

[0324]2,4-dichloro-6-methyl-N-(3-pyridin-3-yl-1,2,4-thiadiazol-5-yl)benzenesulfonamide

[0325]2,4-dichloro-N-[3-(2-chloro-5-nitrophenyl)-1,2,4-thiadiazol-5-yl]-6-methylbenzenesulfonamide

[0326]2,4-dichloro-N-[3-(5-chlorothien-2-yl)-1,2,4-thiadiazol-5-yl]-6-methylbenzenesulfonamide

[0327]2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)-N,N-dipropylacetamide

[0328]3-chloro-2-methyl-N-[3-(2-oxo-2-piperazin-1-ylethyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide

[0329]2,4-dichloro-N-[3-(2,5-dimethyl-3-furyl)-1,2,4-thiadiazol-5-yl]-6-methylbenzenesulfonamide

[0330]N-[3-(3-chlorothien-2-yl)-1,2,4-thiadiazol-5-yl]-4-propylbenzenesulfonamide

[0331]3-chloro-N-[3-(3-chlorothien-2-yl)-1,2,4-thiadiazol-5-yl]-2-methylbenzenesulfonamide

[0332]2,4,6-trichloro-N-[3-(3-chlorothien-2-yl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide

[0333]2,4-dichloro-N-[3-chlorothien-2-yl)-1,2,4-thiadiazol-5-yl]-6-methylbenzenesulfonamide

[0334]2,4-dichloro-N-[3-(2-chlorophenyl)-1,2,4-thiadiazol-5-yl]-6-methylbenzenesulfonamide

[0335]4-bromo-2-methyl-N-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide

[0336]N-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5-yl]-2,4-bis(trifluoromethyl)benzenesulfonamide

[0337]2-methyl-N-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5-yl]-4-(trifluoromethoxy)benzenesulfonamide

[0338]N-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5-yl]-4-phenoxybenzenesulfonamide

[0339]4-chloro-2,6-dimethyl-N-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide

[0340]2,4-dichloro-N-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide

[0341] tert-butyl4-[(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)acetyl]piperazine-1-carboxylate

[0342]2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)-N,N-dimethylacetamide

[0343]3-chloro-2-methyl-N-{3-[2-(pyridin-3-yloxy)ethyl]-1,2,4-thiadiazol-5-yl}benzenesulfonamide

[0344]2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)-N-isopropyl-N-methylacetamide

[0345]2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)-N-ethyl-N-methylacetamide

[0346]3-chloro-2-methyl-N-[3-(2-oxo-2-thiomorpholin-4-ylethyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide

[0347]3-chloro-2-methyl-N-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide

[0348]2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)-N,N-diisopropylacetamide

[0349]3-chloro-2-methyl-N-[3-(2-oxo-2-pyrrolidin-1-ylethyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide

[0350]3-chloro-2-methyl-N-[3-(2-oxo-2-piperidin-1-ylethyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide

[0351]3-chloro-2-methyl-N-[3-(morpholin-4-ylmethyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide

[0352]3-chloro-N-{3-[2-(1H-imidazol-1-yl)ethyl]-1,2,4-thiadiazol-5-yl}-2-methylbenzenesulfonamide

[0353]2,4,5-trichloro-N-[3-(3-chlorothien-2-yl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide

[0354]2,3,4-trichloro-N-[3-(3-chlorothien-2-yl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide

[0355]2,3,4-trichloro-N-[3-(2-chlorophenyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide

[0356]N-[4-(5-{[(4-bromo-2,5-difluorophenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)phenyl]acetamide

[0357]4-bromo-N-[3-(3-chlorothien-2-yl)-1,2,4-thiadiazol-5-yl]-2,5-difluorobenzenesulfonamide

[0358]4,5-dichloro-N-[3-(2-chlorophenyl)-1,2,4-thiadiazol-5-yl]thiophene-2-sulfonamide

[0359]N-[4-(5-{[(2,4,5-trichlorophenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)phenyl]actamide

[0360]4-bromo-5-chloro-N-[3-(3-chlorothien-2-yl)-1,2,4-thiadiazol-5-yl]thiophene-2-sulfonamide

[0361]3-bromo-5-chloro-N-[3-(2-chlorophenyl)-1,2,4-thiadiazol-5-yl]thiophene-2-sulfonamide

[0362]N-[4-(5-{[(2,6-dichlorophenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)phenyl]acetamide

[0363]2,6-dichloro-N-[3-(3-chlorothien-2-yl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide

[0364]N-[2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)ethyl]acetamide

[0365]3-chloro-2-methyl-N-(3-{2-[(methylsulfonyl)amino]ethyl}-1,2,4-thiadiazol-5-yl)benzenesulfonamide

[0366]3-chloro-2-methyl-N-{3-[2-(3-oxo-1,4-oxazepan-4-yl)ethyl]-1,2,4-thiadiazol-5-yl}benzenesulfonamide

[0367]3-chloro-2-methyl-N-{3-[2-(2-oxopyrrolidin-1-yl)ethyl]-1,2,4-thiadiazol-5-yl}benzenesulfonamide

[0368]2,3,4-trichloro-N-{3-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1,2,4-thiadiazol-5-yl}benzenesulfonamide

[0369]N-[3-(2-chloro-6-fluorophenyl)-1,2,4-thiadiazol-5-yl]-4-propylbenzenesulfonamide

[0370]4-bromo-N-{3-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1,2,4-thiadiazol-5-yl}-2,5-difluorobenzenesulfonamide

[0371]4,5-dichloro-N-[3-(2-chloro-6-fluorophenyl)-1,2,4-thiadiazol-5-yl]thiophene-2-sulfonamide

[0372]4-bromo-5-chloro-N-{3-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1,2,4-thiadiazol-5-yl}thiophene-2-sulfonamide

[0373]2,4-dichloro-N-[3-(2-chloro-6-fluorophenyl)-1,2,4-thiadiazol-5-yl]-6-methylbenzenesulfonamide

[0374]4-bromo-N-[3-(2-chloro-6-fluorophenyl)-1,2,4-thiadiazol-5-yl]-2-methylbenzenesulfonamide

[0375]3-chloro-2-methyl-N-(3-{2-[methyl(methylsulfonyl)amino]ethyl}-1,2,4-thiadiazol-5-yl)benzenesulfonamide

[0376]N-[2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)ethyl]-N-methylcyclopropanecarboxamide

[0377]3-chloro-2-methyl-N-{3-[2-(4-methyl-2-oxopiperazin-1-yl)ethyl]-1,2,4-thiadiazol-5-yl}benzenesulfonamide

[0378]3-chloro-2-methyl-N-[3-(2-{[(trifluoromethyl)sulfonyl]amino}ethyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide

[0379]N-[4-(5-{[(4-bromo-5-chlorothien-2-yl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)phenyl]acetamide

[0380]2,4-dichloro-N-{3-[2-(3-oxomorpholin-4-yl)ethyl]-1,2,4-thiadiazol-5-yl}benzenesulfonamide

[0381]2,4-dichloro-6-methyl-N-{3-[2-(3-oxomotpholin-4-yl)ethyl]-1,2,4-thiadiazol-5-yl}benzenesulfonamide

[0382]2,4,6-trichloro-N-{3-[2-(3-oxomorpholin-4-yl)ethyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide

[0383]4-(2-furyl)-N-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide

[0384]5′-fluoro-2′-methoxy-N-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5-yl]-1,1′-biphenyl-4-sulfonamide

[0385]4-(5-methylthien-2-yl)-N-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide

[0386]3′-acetyl-N-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5-yl]-1,1′-biphenyl-4-sulfonamide

[0387]N-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5-yl]-4′-(trifluoromethoxy)-1,1′-biphenyl-4-sulfonamide

[0388]3′,4′-dichloro-N-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5-yl]-1,1′-biphenyl-4-sulfonamide

[0389]4-(1,3-benzodioxol-5-yl)-N-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide

[0390]4-(5-chlorothien-2-yl)-N-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide

[0391]N-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5-yl]-4-pyridin-4-ylbenzenesulfonamide

[0392]N-[4′-({[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5-yl]amino}sulfonyl)-1,1′-biphenyl-3-yl]acetamide

[0393]N-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5-yl]-4-thien-3-ylbenzenesulfonamide

[0394]N-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5-yl]-4-thien-2-ylbenzenesulfonamide

[0395]4′-(methylthio)-N-[3-(²-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5-yl]-1,1′-biphenyl-4-sulfonamide

[0396]N-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5-yl]-3′,5′-bis(trifluoromethyl)-1,1′-biphenyl-4-sulfonamide

[0397]4′-chloro-N-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5-yl]-1,1′-biphenyl-4-sulfonamide

[0398]N-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5-yl]-3′-nitro-1,1′-biphenyl-4-sulfonamide

[0399]3-chloro-2-methyl-N-[3-(2-{methyl[(trifluoromethyl)sulfonyl]amino}ethyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide

[0400]N-[2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)ethyl]-1-methyl-1H-imidazole-4-sulfonamide

[0401]3-chloro-N-{3-[2-(2-hydroxy-3-oxomorpholin-4-yl)ethyl]-1,2,4-thiadiazol-5-yl}-2-methylbenzenesulfonamide

[0402]4,5-dichloro-N-{3-[2-(3-oxomorpholin-4-yl)ethyl]-1,2,4-thiadiazol-5-yl}thiophene-2-sulfonamide

[0403]N-{3-[2-(3-oxomorpholin-4-yl)ethyl]-1,2,4-thiadiazol-5-yl}-4-phenoxybenzenesulfonamide

[0404]3-fluoro-N-{3-[²-(3-oxomorpholin-4-yl)ethyl]-1,2,4-thiadiazol-5-yl}benzenesulfonamide

[0405]N-{3-[2-(3-oxomorpholin-4-yl)ethyl]-1,2,4-thiadiazol-5-yl}-5-pyridin-2-ylthiophene-2-sulfonamide

[0406]N-{2-chloro-4-[({3-[2-(3-oxomorpholin-4-yl)ethyl]-1,2,4-thiadiazol-5-yl}amino)sulfonyl]phenyl}acetamide

[0407] Another object of the present invention is a compound asdescribed above for medical use.

[0408] Another object of the present invention is a method for thetreatment or prevention of diabetes, syndrome X, obesity, glaucoma,hyperlipidemia, hyperglycemia, hyperinsulinemia, hypertension,osteoporosis, dementia, depression, virus diseases or inflammatorydisorders without causing hypoglycemia and to achieve immuno-modulation,preferably tuberculosis, lepra and psoriasis, said method comprisingadministering to a mammal, including a human, in need of such treatment(e.g., identified as in need thereof) an effective amount of a compoundof formula (I) or a composition having a compound of formula (I) in it:

[0409] wherein

[0410] T is an aryl ring or heteroaryl ring, optionally independentlysubstituted by [R]_(n), wherein n is an integer 0-5, and R is hydrogen,aryl, heteroaryl, a heterocyclic ring, optionally halogenatedC₁₋₆-alkyl, optionally halogenated C₁₋₆-alkoxy, C₁₋₆-alkylsulfonyl,carboxy, cyano, nitro, halogen, amine which is optionally mono- ordi-substituted, amide which is optionally mono- or di-substituted,aryloxy, arylsulfonyl, arylamino, wherein aryl, heteroaryl and aryloxyresidues and heterocyclic rings can further be optionally substituted inone or more positions independently of each other by C₁₋₆-acyl,C₁₋₆-alkylthio, cyano, nitro, hydrogen, halogen, optionally halogenatedC₁₋₆-alkyl, optionally halogenated C₁₋₆-alkoxy, amide which isoptionally mono- or di-substituted, (benzoylamino)methyl, carboxy,2-thienylmethylamino or({[4-(2-ethoxy-2-oxoethyl)-1,3-thiazol-2-yl]amino}carbonyl);

[0411] R¹ is hydrogen or C₁₋₆-alkyl;

[0412] A₁ and A₂ are a nitrogen atom or C-Z, provided that A₁ and A₂have different meanings, wherein:

[0413] Z is selected from an aryl ring or heteroaryl ring, which canfurther be optionally substituted in one or more positions independentlyof each other by hydrogen, C₁₋₆-alkyl, halogenated C₁₋₆-alkyl, halogen,C₁₋₆-alkoxy, nitro, C₁₋₆-alkoxycarbonyl, C₁₋₆-alkylsulfonyl, acetylaminoor aryloxy, wherein the aryloxy can further be optionally substituted inone or more positions independently of each other by hydrogen andhalogen; or is X—Y—R², wherein

[0414] X is CH₂ or CO;

[0415] Y is CH₂, CO or a single bond;

[0416] R² is selected from C₁₋₆-alkyl, azido, arylthio, heteroarylthio,halogen, hydroxymethyl, 2-hydroxyethylaminomethyl,methylsulfonyloxymethyl, 3-oxo-4-morpholinolinylmethylene,C₁₋₆-alkoxycarbonyl, 5-methyl-1,3,4-oxadiazol-2-yl;

[0417] NR³R⁴, wherein R³ and R⁴ are each independently selected fromhydrogen, C₁₋₆-alkyl, optionally halogenated C₁₋₆-alkylsulfonyl,C₁₋₆-alkoxy, 2-methoxyethyl, 2-hydroxyethyl, 1-methylimidazolylsulfonyl,C₁₋₆-acyl, cyclohexylmethyl, cyclopropanecarbonyl, aryl, optionallyhalogenated arylsulfonyl, furylcarbonyl, tetrahydro-2-furanylmethyl,N-carbethoxypiperidyl, or C₁₋₆-alkyl substituted with one or more aryl,heterocyclic or heteroaryl, or

[0418] NR³R⁴ represent together heterocyclic systems which can beimidazole, piperidine, pyrrolidine, piperazine, morpholine, oxazepine,oxazole, thiomorpholine, 1,1-dioxidothiomorpholine,2-(3,4-dihydro-2(1H)isoquinolinyl), (1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl, which heterocyclic systems canbe optionally substituted by C₁₋₆-alkyl, C₁₋₆-acyl, hydroxy, oxo,t-butoxycarbonyl;

[0419] OCONR³R⁴, wherein R³ and R⁴ are each independently selected fromhydrogen, C₁₋₆-alkyl or form together with the N-atom to which they areattached morpholinyl;

[0420] R⁵O, wherein R⁵ is hydrogen, optionally halogenated C₁₋₆-alkyl,aryl, heteroaryl, C₁₋₆-acyl, C₁₋₆-alkylsulfonyl, arylcarbonyl,heteroarylcarbonyl, 2-carbomethoxyphenyl;

[0421] or a salt, hydrate or solvate thereof.

[0422] In another aspect, this invention features a method forinhibiting a human 11-β-hydroxysteroid dehydrogenase type 1 enzyme. Themethod includes administering to a subject (e.g., mammal, human, oranimal) in need thereof (e.g., identified as in need thereof) aneffective amount of a compound of any of the formulae delineated hereinor a composition comprising any of the formulae herein.

[0423] The present invention also features a method for treating11-β-hydroxysteroid dehydrogenase type 1 enzyme-mediated disorders. Themethod includes administering to a subject (e.g., mammal, human, oranimal) in need thereof (e.g., identified as in need thereof) aneffective amount of a compound of any of the formulae delineated hereinor a composition comprising any of the formulae delineated herein. The11-β-hydroxysteroid dehydrogenase type 1 enzyme-mediated disorder is anydisorder or symptom wherein the 11-β-hydroxysteroid dehydrogenase type 1enzyme is involved in the process or presentation of the disorder or thesymptom. The 11-β-hydroxysteroid dehydrogenase type 1 enzyme-mediateddisorders include, but are not limited to, diabetes, syndrome X,obesity, glaucoma, hyperlipidemia, hyperglycemia, hyperinsulinemia,hypertension, osteoporosis, dementia, depression, virus diseases,inflammatory disorders, and immuno-modulation. Preferred examples ofimmuno-modulation are tuberculosis, lepra, and psoriasis. When thedisorder is hyperglycemia, the treatment thereof does not causehypoglycemia.

[0424] The methods delineated herein can also include the step ofidentifying that the subject is in need of treatment of the diseases ordisorders described above. The identification can be in the judgment ofa subject or a health professional and can be a subjective (e.g.,opinion) or objective (e.g., measurable by a test or diagnostic method).

[0425] These compounds may also be used in the manufacture of amedicament for the prevention, management or treatment of diabetes,syndrome X, obesity, glaucoma, hyperlipidemia, hyperglycemia,hyperinsulinemia, hypertension, osteoporosis, dementia, depression,virus diseases or inflammatory disorders without causing hypoglycemiaand to achieve immuno-modulation. Preferred examples ofimmuno-modulation are tuberculosis, lepra, and psoriasis.

[0426] It is preferred that:

[0427] T is selected from 5-chloro-1,3-dimethyl-1H-pyrazol-4-yl;4-chloro-2,3,1-benzoxadiazolyl; 5-(dimethylamino)-1-naphthyl;1-methylimidazol-4-yl; 1-naphthyl; 2-naphthyl; 8-quinolinyl;

[0428] thienyl substituted with one or more of (benzoylamino)methyl,bromo, chloro, 3-isoxazolyl, 2-(methylsulfanyl)-4-pyrimidinyl,1-methyl-5-(trifluoromethyl)pyrazol-3-yl, phenylsulfonyl, pyridyl;

[0429] phenyl substituted with one or more of acetylamino,3-acetylaminophenyl, 3-acetylphenyl, benzeneamino, 1,3-benzodioxol-5-yl,2-benzofuryl, benzylamino, 3,5-bis(trifluoromethyl)phenyl, bromo,butoxy, carboxy, chloro, 4-carboxyphenyl, 3-chloro-2-cyanophenoxy,4-chlorophenyl, 5-chloro-2-thienyl, cyano, 3,4-dichlorophenyl,({[4-(2-ethoxy-2-oxoethyl)-1,3-thiazol-2-yl]amino}carbonyl), fluoro,5-fluoro-2-methoxyphenyl, 2-furyl, hydrogen, iodo, isopropyl,methanesulfonyl, methoxy, methyl, 4-methyl-1-piperazinyl,4-methyl-1-piperidinyl, 4-methylsulfanylphenyl, 5-methyl-2-thienyl,4-morpholinyl, nitro, 3-nitrophenyl, phenoxy, phenyl, n-propyl,4-pyridyl, 3-pyridylmethylamino, 1-pyrrolidinyl, 2-thienyl, 3-thienyl,2-thienylmethylamino, trifluoromethoxy, 4-trifluoromethoxyphenyl,trifluoromethyl; or

[0430] R¹ is hydrogen or methyl;

[0431] A₁ and A₂ are a nitrogen atom or C-Z, provided that A₁ and A₂have different meanings, wherein:

[0432] Z is selected from 1-benzothien-3-yl, 3-(2,5-dimethylfuryl),pyridinyl; thienyl optionally substituted with one or more of chloro,methylsulfonyl; phenyl optionally substituted with one or more ofethoxycarbonyl, nitro, fluoro, methyl, methoxy, acetylamino, chloro,4-chlorophenoxy, trifluoromethyl; or is X—Y—R², wherein

[0433] X is CH₂ or CO;

[0434] Y is CH₂, CO or a single bond;

[0435] R² is selected from n-propyl, azido, bromo, chloro,2-pyridinylsulfanyl, 3-oxo-4-morpholinolinylmethylene, ethoxycarbonyl,5-methyl-1,3,4-oxadiazol-2-yl, hydroxymethyl, 2-hydroxyethylaminomethyl,methylsulfonyloxymethyl;

[0436] NR³R⁴, wherein R³ and R⁴ are each independently selected fromacetyl, benzhydryl, 1,3-benzodioxol-5-ylmethyl, benzyl,3-chloro-2-methylphenylsulfonyl, cyclohexyl, cyclohexylmethyl,cyclopropanecarbonyl, ethyl, 2-furylcarbonyl, 2-furylmethyl, hydrogen,2-hydroxyethyl, 2-(1H-indol-3-yl)ethyl, isopropyl, methoxy,2-methoxyethyl, methyl, 4-(1-methylimidazolyl)sulfonyl, methylsulfonyl,phenyl, (1S)-phenylethyl, n-propyl, tetrahydro-2-furanylmethyl,trifluoromethylsulfonyl, N-carbethoxypiperidyl; or

[0437] NR³R⁴ represent together 4-acetylpiperazinyl,4-t-butoxycarbonylpiperazinyl, 2-(3,4-dihydro-2(1H)isoquinolinyl),(2R,6S)-2,6-dimethylmorpholinyl, (2R)-2,4-dimethyl-1-piperazinyl,2-hydroxy-3-oxomorpholinyl, imidazolyl, 2-methyl-3-oxomorpholinyl,4-methyl-2-oxopiperazinyl, 4-methylpiperazinyl, morpholinyl,(1S,4S)-2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl, 2-oxoimidazolinyl,3-oxomorpholinyl, 3-oxo-1,4-oxazepinyl, 2-oxooxazolinyl, piperazinyl;piperidinyl; pyrrolidinyl; pyrrolidonyl, thiomorpholinyl;1,1-dioxido-thiomorpholinyl;

[0438] OCONR³R⁴, wherein R³ and R⁴ are each independently selected fromethyl, hydrogen or form together with the N-atom to which they areattached morpholinyl;

[0439] R⁵O, wherein R⁵ is acetyl, benzoyl, benzyl, ethyl, 2-fluoroethyl,2-furylcarbonyl, hydrogen, isobutyryl, isopropyl, methyl,2-carbomethoxyphenyl, methylsulfonyl, phenyl, n-propionyl, 3-pyridinyl,2,2,2-trifluoroethyl.

[0440] Specific examples of compounds according to the present inventionare given above and also the following compounds:

[0441]3-chloro-N-{5-[2-(diethylamino)ethyl]-1,3,4-thiadiazol-2-yl}-2-methylbenzenesulfonamide

[0442] N-(5-phenyl-1,3,4-thiadiazol-2-yl)-4-propylbenzenesulfonamide

[0443]3-chloro-2-methyl-N-(5-phenyl-1,3,4-thiadiazol-2-yl)benzenesulfonamide

[0444]3-chloro-N-[5-(4-fluoro-3-methylphenyl)-1,3,4-thiadiazol-2-yl]-2-methylbenzenesulfonamide

[0445]2,4,6-trichloro-N-(5-phenyl-1,3,4-thiadiazol-2-yl)benzenesulfonamide

[0446] N-(5-phenyl-1,3,4-thiadiazol-2-yl)-1,1′-biphenyl-4-sulfonamide

[0447]2,4-dichloro-6-methyl-N-(5-phenyl-1,3,4-thiadiazol-2-yl)benzenesulfonamide

[0448]N-[4-(5-{[(4-propylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)phenyl]acetamide

[0449]N-[5-(2-chloro-5-nitrophenyl)-1,3,4-thiadiazol-2-yl]-4-propylbenzenesulfonamide

[0450]N-[5-(2-chlorophenyl)-1,3,4-thiadiazol-2-yl]-4-propylbenzenesulfonamide

[0451]3-chloro-N-[5-(2-chloro-5-nitrophenyl)-1,3,4-thiadiazol-2-yl]-2-methylbenzenesulfonamide

[0452]3-chloro-N-[5-(2-chlorophenyl)-1,3,4-thiadiazol-2-yl]-2-methylbenzenesulfonamide

[0453]N-[4-(5-{[(2,4,6-trichlorophenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)phenyl]acetamide

[0454]2,4,6-trichloro-N-[5-(2-chloro-5-nitrophenyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide

[0455]2,4,6-trichloro-N-[5-(2-chlorophenyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide

[0456]N-(4-{5-[(1,1′-biphenyl-4-ylsulfonyl)amino]-1,3,4-thiadiazol-2-yl}phenyl)acetamide

[0457]N-[5-(2-chloro-5-nitrophenyl)-1,3,4-thiadiazol-2-yl]-1,1′-biphenyl-4-sulfonamide

[0458]N-[5-(2-chlorophenyl)-1,3,4-thiadiazol-2-yl]-1,1′-biphenyl-4-sulfonamide

[0459]N-[4-(5-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)phenyl]acetamide

[0460]2,4-dichloro-N-[5-(2-chloro-5-nitrophenyl)-1,3,4-thiadiazol-2-yl]-6-methylbenzenesulfonamide

[0461]2,4-dichloro-N-[5-(2-chlorophenyl)-1,3,4-thiadiazol-2-yl]-6-methylbenzenesulfonamide

[0462]2,3,4-trichloro-N-[5-(2-chlorophenyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide

[0463]N-[4-(5-{[(4-bromo-2,5-difluorophenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)phenyl]acetamide

[0464]4,5-dichloro-N-[5-(2-chlorophenyl)-1,3,4-thiadiazol-2-yl]thiophene-2-sulfonamide

[0465]N-[4-(5-{[(2,4,5-trichlorophenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)phenyl]acetamide

[0466]3-bromo-5-chloro-N-[5-(2-chlorophenyl)-1,3,4-thiadiazol-2-yl]thiophene-2-sulfonamide

[0467]N-[4-(5-{[(2,6-dichlorophenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)phenyl]acetamide

[0468]2,3,4-trichloro-N-{5-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1,3,4-thiadiazol-2-yl}benzenesulfonamide

[0469]N-[5-(2-chloro-6-fluorophenyl)-1,3,4-thiadiazol-2-yl]-4-propylbenzenesulfonamide

[0470]4-bromo-N-{5-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1,3,4-thiadiazol-2-yl}-2,5-difluorobenzenesulfonamide

[0471]4,5-dichloro-N-[5-(2-chloro-6-fluorophenyl)-1,3,4-thiadiazol-2-yl]thiophene-2-sulfonamide

[0472]4-bromo-5-chloro-N-{5-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1,3,4-thiadiazol-2-yl}thiophene-2-sulfonamide

[0473]2,4-dichloro-N-[5-(2-chloro-6-fluorophenyl)-1,3,4-thiadiazol-2-yl]-6-methylbenzenesulfonamide

[0474]4-bromo-N-[5-(2-chloro-6-fluorophenyl)-1,3,4-thiadiazol-2-yl]-2-methylbenzenesulfonamide

[0475]N-[4-(5-{[(4-bromo-5-chlorothien-2-yl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)phenyl]acetamide.

[0476] Another object of the present invention is a pharmaceuticalcomposition comprising at least one compound of formula (I) as definedabove, and a pharmaceutically acceptable carrier.

[0477] Also within the scope of this invention is a method for making acompound of formula (I). The method includes taking any intermediatecompound delineated herein, reacting it with one or more reagents toform a compound of formula (I) including any processes specificallydelineated herein.

[0478] Other features and advantages of the invention will be apparentfrom the detailed description and claims.

DETAILED DESCRIPTION OF THE INVENTION

[0479] The compounds according to the present invention may be used inseveral indications which involve 11-β-hydroxysteroid dehydrogenase type1 enzyme. Thus, the compounds according to the present invention may beused against dementia (see WO97/07789), osteoporosis (see Canalis E1996, Mechanisms of glucocorticoid action in bone: implications toglucocorticoid-induced osteoporosis, Journal of Clinical Endocrinologyand Metabolism, 81, 3441-3447) and may also be used disorders in theimmune system (see Franchimont et al, “Inhibition of Th1 immune responseby glucocorticoids: dexamethasone selectively inhibits IL-12-inducedStat 4 phosphorylation in T lymphocytes”, The journal of Immunology2000, Feb. 15, vol 164 (4), pages 1768-74) and also in the above listedindications.

[0480] The various terms used, separately and in combinations, in theabove definition of the compounds having the formula (I) will beexplained.

[0481] The term “aryl” in the present description is intended to includearomatic rings (monocyclic or bicyclic) having from 6 to 10 ring carbonatoms, such as phenyl (Ph) and naphthyl, which optionally may besubstituted by C₁₋₆-alkyl. Examples of substituted aryl groups arebenzyl, and 2-methylphenyl.

[0482] The term “heteroaryl” means in the present description amonocyclic, bi- or tricyclic aromatic ring system (only one ring need tobe aromatic) having from 5 to 14, preferably 5 to 10 ring atoms such as5, 6, 7, 8, 9 or 10 ring atoms (mono- or bicyclic), in which one or moreof the ring atoms are other than carbon, such as nitrogen, sulfur,oxygen and selenium as part of the ring system. Examples of suchheteroaryl rings are pyrrole, imidazole, thiophene, furan, thiazole,isothiazole, thiadiazole, oxazole, isoxazole, oxadiazole, pyridine,pyrazine, pyrimidine, pyridazine, pyrazole, triazole, tetrazole,chroman, isochroman, quinoline, quinoxaline, isoquinoline, phthalazine,cinnoline, quinazoline, indole, isoindole, indoline, isoindoline,benzothiophene, benzofuran, isobenzofuran, benzoxazole,2,1,3-benzoxadiazole, benzothiazole, 2,1,3-benzothiazole,2,1,3-benzoselenadiazole, benzimidazole, indazole, benzodioxane, indane,1,2,3,4-tetrahydroquinoline, 3,4-dihydro-2H-1,4-benzoxazine,1,5-naphthyridine, 1,8-naphthyridine, acridine, fenazine and xanthene.

[0483] The term “heterocyclic” in the present description is intended toinclude unsaturated as well as partially and fully saturated mono-, bi-and tricyclic rings having from 4 to 14, preferably 4 to 10 ring atomshaving one or more heteroatoms (e.g., oxygen, sulfur, or nitrogen) aspart of the ring system and the reminder being carbon, such as, forexample, the heteroaryl groups mentioned above as well as thecorresponding partially saturated or fully saturated heterocyclic rings.Exemplary saturated heterocyclic rings are azetidine, pyrrolidine,piperidine, piperazine, morpholine, thiomorpholine and 1,4-oxazepane.

[0484] C₁₋₆-alkyl in the compound of formula (I) according to thepresent application, which may be straight, branched or cyclic, ispreferably C₁₋₄-alkyl. Exemplary alkyl groups include methyl, ethyl,n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, isopentyl,hexyl, isohexyl, and cyclohexyl. For parts of the range “C₁₋₆-alkyl” allsubgroups thereof are contemplated such as C₁₋₅-alkyl, C₁₋₄-alkyl,C₁₋₃-alkyl, C₁₋₂-alkyl, C₂₋₆-alkyl, C₂₋₅-alkyl, C₂₋₄-alkyl, C₂₋₃-alkyl,C₃₋₆-alkyl, C₄₋₅-alkyl, etc.

[0485] C₁₋₆-alkoxy, in the compound of formula (I) according to thepresent application may be straight or branched, is preferablyC₁₋₄-alkoxy. Exemplary alkoxy groups include methoxy, ethoxy, propoxy,isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy,hexyloxy, and isohexyloxy. For parts of the range “C₁₋₆-alkoxy” allsubgroups thereof are contemplated such as C₁₋₅-alkoxy, C₁₋₄-alkoxy,C₁₋₃-alkoxy, C₁₋₂-alkoxy, C₂₋₆-alkoxy, C₂₋₅-alkoxy, C₂₋₄-alkoxy,C₂₋₃-alkoxy, C₃₋₆-alkoxy, C₄₋₅-alkoxy, etc.

[0486] C₁₋₆-acyl, in the compound of formula (I) according to thepresent application may be saturated or unsaturated and is preferablyC₁₋₄-acyl. Exemplary acyl groups include formyl, acetyl, propionyl,butyryl, isobutyryl, valeryl, isovaleryl, butenoyl (e.g. 3-butenoyl),hexenoyl (e.g. 5-hexenoyl). For parts of the range “C₁₋₆-acyl” allsubgroups thereof are contemplated such as C₁₋₅-acyl, C₁₋₄-acyl,C₁₋₃-acyl, C₁₋₂-acyl, C₂₋₆-acyl, C₂₋₅-acyl, C₂₋₄-acyl, C₂₋₃-acyl,C₃₋₆-acyl, C₄₋₅-acyl, etc.

[0487] C₂₋₆-alkenyl in the compound of formula (I) according to thepresent application, which may be straight, branched or cyclic, ispreferably C₂₋₄-alkenyl. Exemplary alkenyl groups include vinyl,1-propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 1-pentenyl,2-pentenyl, 1-hexenyl, 2-hexenyl, and 1-cyclohexenyl. For parts of therange “C₂₋₆-alkenyl” all subgroups thereof are contemplated such asC₂₋₅-alkenyl, C₂₋₄-alkenyl, C₂₋₃-alkenyl, C₃₋₆-alkenyl, C₄₋₅-alkenyl,etc.

[0488] The term “halogen” in the present description is intended toinclude fluorine, chlorine, bromine and iodine.

[0489] The term “sulfanyl” in the present description means a thiogroup.

[0490] With the expression “mono- or di-substituted” is meant in thepresent description that the functionalities in question may besubstituted with independently C₁₋₆-acyl, C₂₋₆-alkenyl,C₁₋₆-(cyclo)alkyl, aryl, pyridylmethyl, or heterocyclic rings e.g.azetidine, pyrrolidine, piperidine, piperazine, morpholine andthiomorpholine, which heterocyclic rings optionally may be substitutedwith C₁₋₆-alkyl. With the expression “optionally mono- or disubstituted”is meant in the present description that the functionalities in questionmay also be substituted with independently hydrogen.

[0491] Combinations of substituents and variables envisioned by thisinvention are only those that result in the formation of stablecompounds. The term “stable”, as used herein, refers to compounds whichpossess stability sufficient to allow manufacture and which maintainsthe integrity of the compound for a sufficient period of time to beuseful for the purposes detailed herein (e.g., therapeuticadministration to a subject for the treatment of disease, 11-β-HSD1inhibition, 11-β-HSD1-mediated disease).

[0492] The term “prodrug forms” in the present description means apharmacologically acceptable derivative, such as an ester or an amide,which derivative is biotransformed in the body to form the active drug(see Goodman and Gilman's, The Pharmacological basis of Therapeutics,8^(th) ed., McGraw-Hill, Int. Ed. 1992, “Biotransformation of Drugs, p.13-15). “Pharmaceutically acceptable” means in the present descriptionbeing useful in preparing a pharmaceutical composition that is generallysafe, non-toxic and neither biologically nor otherwise undesirable andincludes being useful for veterinary use as well as human pharmaceuticaluse.

[0493] “Pharmaceutically acceptable salts” mean in the presentdescription salts which are pharmaceutically acceptable, as definedabove, and which possess the desired pharmacological activity. Suchsalts include acid addition salts formed with organic and inorganicacids, such as hydrogen chloride, hydrogen bromide, hydrogen iodide,sulfuric acid, phosphoric acid, acetic acid, glycolic acid, maleic acid,malonic acid, oxalic acid, methanesulfonic acid, trifluoroacetic acid,fumaric acid, succinic acid, tartaric acid, citric acid, benzoic acid,ascorbic acid and the like. Base addition salts may be formed withorganic and inorganic bases, such as sodium, ammonia, potassium,calcium, ethanolamine, diethanolamine, N-methylglucamine, choline andthe like. Included in the invention are pharmaceutically acceptablesalts or compounds of any of the formulae herein.

[0494] Pharmaceutical compositions according to the present inventioncontain a pharmaceutically acceptable carrier together with at least oneof the compounds comprising the formula (I) as described herein above,dissolved or dispersed therein as an active, antimicrobial, ingredient.In a preferred embodiment, the therapeutic composition is notimmunogenic when administered to a human patient for therapeuticpurposes, unless that purpose is to induce an immune response.

[0495] The preparation of a pharmacological composition that containsactive ingredients dissolved or dispersed therein is well understood inthe art. Typically such compositions are prepared as sterile injectableseither as liquid solutions or suspensions, aqueous or non-aqueous,however, solid forms suitable for solution, or suspensions, in liquidprior to use can also be prepared. The preparation can also beemulsified.

[0496] The active ingredient may be mixed with excipients, which arepharmaceutically acceptable and compatible with the active ingredientand in amounts suitable for use in the therapeutic methods describedherein. Suitable excipients are, for example, water, saline, dextrose,glycerol, ethanol or the like and combinations thereof. In addition, ifdesired, the composition may contain minor amounts of auxiliarysubstances such as wetting or emulsifying agents, pH buffering agentsand the like which enhance the effectiveness of the active ingredient.Adjuvants may also be present in the composition.

[0497] Pharmaceutically acceptable carriers are well known in the art.Exemplary of liquid carriers are sterile aqueous solutions that containno materials in addition to the active ingredients and water, or containa buffer such as sodium phosphate at physiological pH value,physiological saline or both, such as phosphate-buffered saline. Stillfurther, aqueous carriers can contain more than one buffer salt, as wellas salts such as sodium and potassium chlorides, dextrose, propyleneglycol, polyethylene glycol and other solutes.

[0498] Liquid compositions can also contain liquid phases in addition toand to the exclusion of water. Exemplary of such additional liquidphases are glycerine, vegetable oils such as cottonseed oil, organicesters such as ethyl oleate, and water-oil emulsions.

[0499] The pharmaceutical composition according to one of the preferredembodiments of the present invention comprising compounds comprising theformula (I), may include pharmaceutically acceptable salts of thatcomponent therein as set out above. Pharmaceutically acceptable saltsinclude the acid addition salts (formed with the free amino groups ofthe polypeptide) that are formed with inorganic acids such as, forexample, hydrochloric or phosphoric acids, or such organic acids asacetic acid, tartaric acid, mandelic acid and the like. Salts formedwith the free carboxyl groups can also be derived from inorganic basessuch as, for example, sodium, potassium, ammonium, calcium or ferrichydroxides, and such organic bases as isopropylamine, trimethylamine,2-ethylamino ethanol, histidine, procaine and the like.

[0500] The preparations according to the preferred embodiments may beadministered orally, topically, intraperitoneally, intraarticularly,intracranially, intradermally, intramuscularly, intraocularly,intrathecally, intravenously, subcutaneously. Other routes are known tothose of ordinary skill in the art.

[0501] The orally administrable compositions according to the presentinvention may be in the form of tablets, capsules, powders, granules,lozenges, liquid or gel preparations, such as oral, topical or sterileparenteral solutions or suspensions. Tablets and capsules for oraladministration may be in unit dose presentation form and may containconventional excipients such as binding agents, for example syrup,acacia, gelatin, sorbitol, traganath or polyvinyl-pyrrolidone; fillerse.g. lactose, sugar, maize-starch, calcium phosphate, sorbitol orglycine; tabletting lubricant e.g. magnesium stearate, talc,polyethylene glycol or silica; disintegrants e.g. potato starch, oracceptable wetting agents such as sodium lauryl sulfate. The tablets maybe coated according to methods well known in normal pharmaceuticalpractice. Oral liquid preparations may be in the form of e.g. aqueous oroily suspensions, solutions, emulsions, syrups or elixirs or may bepresented as a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents, e.g. sorbitol, syrup,methyl cellulose, glucose syrup, gelatin hydrogenated edible fats;emulsifying agents e.g. lecithin, sorbitan monooleate or acacia,non-aqueous vehicles (which may include edible oils), e.g. almond oil,fractionated coconut oil, oily esters such as glycerine, propyleneglycol, or ethyl alcohol; preservatives e.g. methyl or propylp-hydroxybenzoate or sorbic acid, and if desired conventional flavouringor colouring agents.

[0502] “An effective amount” refers to an amount of a compound whichconfers a therapeutic effect on the treated subject. The therapeuticeffect may be objective (i.e., measurable by some test or marker) orsubjective (i.e., subject gives an indication of or feels an effect). Apharmaceutical composition according to the present invention, maycomprise typically an amount of at least 0.1 weight percent of compoundcomprising the formula (I) per weight of total therapeutic composition.A weight percent is a ratio by weight of total composition. Thus, forexample, 0.1 weight percent is 0.1 grams of compound comprising theformula (I) per 100 grams of total composition. A suitable daily oraldose for a mammal, preferably a human being, may vary widely dependingon the condition of the patient. However a dose of compound comprisingthe formula (I) of about 0.1 to 300 mg/kg body weight may beappropriate.

[0503] The compositions according to the present invention may also beused veterinarily and thus they may comprise a veterinarily acceptableexcipient or carrier. The compounds and compositions may be thusadministered to animals, e.g., cats, dogs, or horses, in treatmentmethods.

[0504] The compounds of the present invention in labelled form, e.g.isotopically labelled, may be used as a diagnostic agent.

[0505] This invention relates to methods of making compounds of any ofthe formulae herein comprising reacting any one or more of the compoundsof the formulae delineated herein, including any processes delineatedherein. The compounds of formula (I) above may be prepared by, or inanalogy with, conventional methods, and especially according to or inanalogy with the following methods. Further, the pharmacology in-vitrowas studied using the following reagents and methods.

[0506] The chemicals used in the synthetic routes delineated herein mayinclude, for example, solvents, reagents, catalysts, and protectinggroup and deprotecting group reagents. The methods described above mayalso additionally include steps, either before or after the stepsdescribed specifically herein, to add or remove suitable protectinggroups in order to ultimately allow synthesis of the compounds. Inaddition, various synthetic steps may be performed in an alternatesequence or order to give the desired compounds. Synthetic chemistrytransformations and protecting group methodologies (protection anddeprotection) useful in synthesizing applicable compounds are known inthe art and include, for example, those described in R. Larock,Comprehensive Organic Transformations, VCH Publishers (1989); T. W.Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3^(rd)Ed., John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser andFieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); andL. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, JohnWiley and Sons (1995) and subsequent editions thereof.

[0507] All publications mentioned herein are hereby incorporated byreference. By the expression “comprising” means “including but notlimited to.” Thus, other non-mentioned substances, additives or carriersmay be present.

[0508] The invention will now be described in reference to the followingExamples. These Examples are not to be regarded as limiting the scope ofthe present invention, but shall only serve in an illustrative manner.

EXAMPLES

[0509] Experimental Methods

[0510] Scintillation Proximity Assay

[0511] [1, 2(n)−³H]-cortisone was purchased from Amersham PharmaciaBiotech. Anti-cortisol monoclonal mouse antibody, clone 6D6.7 wasobtained from Immunotech and Scintillation proximity assay (SPA) beadscoated with monoclonal antimouse antibodies were from Amersham PharmaciaBiotech. NADPH, tetrasodium salt was from Calbiochem andglucose-6-phosphate (G-6-P) was supplied by Sigma. The human11-β-hydroxysteroid dehydrogenase type-1 enzyme (11-β-HSD₁) wasexpressed in Pichia pastoris. 18-β-glycyrrhetinic acid (GA) was obtainedfrom Sigma. The serial dilutions of the compounds were performed on aTecan Genesis RSP 150. Compounds to be tested were dissolved in DMSO (1mM) and diluted in 50 mM Tris-HCl, pH 7.2 containing 1 mM EDTA.

[0512] The multiplication of plates was done on a WallacQuadra. Theamount of the product [3H]-cortisol, bound to the beads was determinedin a Packard, Top Count microplate liquid scintillation counter.

[0513] The 11-β-HSD₁ enzyme assay was carried out in 96 well microtiterplates (Packard, Optiplate) in a total well volume of 220 μL andcontained 30 mM Tris-HCl, pH 7.2 with 1 mM EDTA, a substrate mixturetritiated Cortisone/NADPH (175 nM/181 μM), G-6-P (1 mM) and inhibitorsin serial dilutions (9 to 0.15 μM). Reactions were initiated by theaddition of human 11-β-HSD₁, either as Pichia pastoris cell homogenateor microsomes prepared from Pichia pastoris (the final amount of enzymeused was varied between 0.057 to 0.11 mg/mL). Following mixing, theplates were shaken for 30 to 45 minutes at room temperature. Thereactions were terminated with 10 μL 1 mM GA stop solution. Monoclonalmouse antibody was then added (10 μL of 4 μM) followed by 100 μL of SPAbeads (suspended according to the manufacturers instructions).Appropriate controls were set up by omitting the 11-β-HSD₁ to obtain thenon-specific binding (NSB) value.

[0514] The plates were covered with plastic film and incubated on ashaker for 30 minutes, at room temperature, before counting. The amountof [³H]-cortisol, bound to the beads was determined in a microplateliquid scintillation counter.

[0515] The calculation of the K_(i) values for the inhibitors wasperformed by use of Activity Base. The K_(i) value is calculated fromIC₅₀ and the K_(m) value is calculated using the Cheng Prushoff equation(with reversible inhibition that follows the Michaelis-Menten equation):K_(i)=IC₅₀(1+[S]/K_(m)) [Cheng, Y. C.; Prushoff, W. H. Biochem.Pharmacol. 1973, 22, 3099-3108]. The IC₅₀ is measured experimentally inan assay wherein the decrease of the turnover of cortisone to cortisolis dependent on the inhibition potential of each substance. The Kivalues of the compounds of the present invention for the 11-β-HSD1enzyme lie typically between about 10 nM and about 10 βM.

[0516] Compound Preparation

[0517] General:

[0518] For preparative straight phase HPLC purification a Phenomenexcolumn (250×21.1 mm, 10 μm) was used on a Gilson system eluting withethanol in chloroform (gradient from 0-10% in 10 min) with a flow of 20mL/min. Column chromatography was performed on silica using Silica gel60 (230-400 mesh), Merck. Melting points were determined on a Gallenkampapparatus. Elemental analyses were recorded using a Vario EL instrument.HPLC analyses were performed using a Hypersil Elite column (150×4.6 mm,3μ) with a flow of 3 mL/min on a Waters 600E system with monitoring at254 nm. Reverse phase preparative HPLC was carried out on a 100×21.2 mm,5μ Hypersil Elite column eluting with a gradient of 5% ACN in 95% waterto 95% ACN in 5% water (0.2% TFA buffer) over 10 mins at a flow rate of20 mL/min with the UV detector set at 254 nm. Thin layer chromatographywas carried out using pre-coated silica gel F-254 plates (thickness 0.25mm). Electrospray MS spectra were obtained on a Micromass platform LCMSspectrometer. Crude, worked up compounds were purified by flash columnchromatography using pre packed silica SPE columns (10 g silica) on anIsco Foxy 200 Combiflash system, and a gradient of 16.67% ethyl acetatein hexane increasing incrementally to 100% ethyl acetate.

[0519] List of Abbreviations

[0520] ACN=acetonitrile

[0521] DCM=dichloromethane

[0522] DIEA=N,N-diisopropylethylamine

[0523] DMAP=4-dimethylaminopyridine

[0524] DME=ethyleneglycol dimethyl ether

[0525] DMF=dimethylformamide

[0526] DMSO=dimethyl sulfoxide

[0527] EDCI=1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

[0528] EDTA=ethylenediaminetetraacetic acid

[0529] HCOOH=formic acid

[0530] HOAT=1-hydroxy-7-azabenzotriazole

[0531] HOBT=1-hydroxybenzotriazole hydrate

[0532] MTBE=tert-butyl methyl ether

[0533] TEA=triethylamine

[0534] TFA=trifluoroacetic acid

[0535] THF=tetrahydrofuran

[0536] Sulfonamide Couplings:

[0537] Method A:

[0538] 1 Eq of the heterocyclic compound (i e a 1,2,4-thiadiazole or1,3,4-thiadiazole derivative) with an exocyclic amino group wasdissolved in pyridine (0.5 M solution). The sulfonyl chloride (1.2 eq)was added and the reaction mixture was stirred at ambient temperatureunder nitrogen atmosphere for 15 h. The reaction mixture was poured intoaqueous HCl (1 M). If the product precipitated it was collected on afilter and washed with aqueous HCl (1 M) and recrystallised fromethanol. In case an oil was obtained, the crude was extracted with DCMand worked up and purified using standard procedures.

[0539] Method B:

[0540] A solution of the heterocyclic compound (i e a 1,2,4-thiadiazoleor 1,3,4-thiadiazole derivative) with an exocyclic amino group (1 eq),triethylamine (2 eq) and DMAP (1 eq) in DMF (1 M) and DCM (0.225 M) wasdispensed into a reaction vial. The sulfonyl chloride (1.2 eq) wasdissolved in DCM (0.33 M) and added. The reaction mixtures were kept atroom temperature over night. The mixture was then added to petroleumether (10 times reaction volume). After some hours in refrigerator thesupernatants were decanted and (a portion of) the residual materialswere dissolved in DMSO-methanol-acetic acid (300 μL+500 μL+50 μL) andpurified by preparative LCMS (acetonitrile-water gradients). The purestfractions were collected and lyophilized. Alternatively, the crude wasisolated using extractive work-up and purified using standardprocedures.

[0541] Saponifications:

[0542] Method C:

[0543] 1 Eq of the ester was suspended in 95% ethanol (0.1 M) andtreated with KOH (aqueous, 6 eq). Water was added until a clear solutionwas achieved. The reaction mixture was stirred for 2-3 h at ambienttemperature. The solvent was removed under reduced pressure and thecrude was redissolved in water. Addition of conc. HCl until pH 2 gave aprecipitate which was collected on a filter and washed with cold waterand dried.

[0544] Amide Couplings:

[0545] Method D:

[0546] The carboxylic acid ester was dissolved (0.05 M) in a largeexcess of the amine in 40 or 70% water-solution. The reaction mixturewas stirred at ambient temperature over night. The solvent was removedunder reduced pressure and the crude product was purified by flashcolumn chromatography on silica gel eluting with methanol (0→6%) in DCM.

[0547] Method E:

[0548] The carboxylic acid was suspended in DCM (0.05M) followed by theaddition of EDCI (1.1 eq), triethylamine (3 eq), DMAP (0.5 eq) and theamine of choice (1.2 eq). DMF was added when the starting materials didnot dissolve properly. The reaction mixture was stirred at ambienttemperature over night. The organic phase was washed with aqueous HCl (1M), dried over sodium sulfate, filtered and evaporated in vacuo. Thecrude product amide was purified by flash column chromatography onsilica gel, eluting with methanol (1→3→6%) in DCM or ethyl acetate.

[0549] Method F:

[0550] The carboxylic acid was suspended in DCM (0.1 M) and cooled to 0°C. under nitrogen (g) atmosphere. EDCI (1 eq), HOAT (1 eq) or HOBT (1eq) was added, followed by TEA (2.2 eq). After 10 min, the amine ofchoice (1.2 eq) was added and the reaction mixture was allowed to warmto ambient temperature. After 5 h, the DCM phase was washed with aqueousHCl (1 M) and worked up and purified as described in METHOD E.

[0551] Method G:

[0552] Under N₂-atmosphere, aluminium chloride (1 eq) was suspended inDCM (0.1 M) and treated with the amine of choice (4 eq) at ambienttemperature. After 10 min, the alkyl ester (1 eq) was added and thereaction mixture was stirred until starting material had been consumed(TLC). Quenching with saturated aqueous sodium hydrogen carbonate oraqueous HCl (1 M) and extractive workup with ethyl acetate gave thecrude products which were then purified by flash chromatography onsilica gel eluting with DCM/methanol mixtures.

[0553] Acylations:

[0554] Method J:

[0555] To a solution of the alcohol in dry pyridine (0.3 M), 1.1 eq ofacid chloride was added at 0° C. The reaction mixture was stirred atroom temperature for 6 h, concentrated, co-evaporated with acetonitrile,re-dissolved in DCM, washed with aqueous HCl (0.5 M), dried with sodiumsulfate and chromatographed on silica gel using petroleum-ether andethyl acetate as eluents.

[0556] Carbamates:

[0557] Method K:

[0558] To a solution of the alcohol in dry pyridine (0.3 M), 1.5 eq of4-nitrophenyl chloroformate (0.5 M in dry pyridine) was added at 0° C.After the reaction mixture was stirred at room temperature for 12 h, 5eq of primary or secondary amine were added at 0° C. The solution wasstirred at room temperature for 3 h, concentrated, co-evaporated withacetonitrile, re-dissolved in DCM, washed with aqueous HCl (0.5 M) andsaturated aqueous sodium bicarbonate, dried with sodium sulfate andchromatographed on silica gel using DCM and methanol as eluents.

[0559] Sulfonyl Chlorides

[0560] Arylsulfonyl chlorides that were not commercially available wereprepared from the aniline derivatives according to literature procedures(see for instance: Hoffman, R. V. (1981) Org. Synth. 60: 121).

[0561] Preparation of Starting Compounds

[0562] The preparation of thiadiazolyl (lower) alkanoic acid derivativesis described in Teraji, Tsutomu; Sakane, Kazuo; Goto, Jiro. (FujisawaPharmaceutical Co., Ltd., Japan). Brit. UK Pat. Appl. (1981), 13 pp.CODEN: BAXXDU GB 2068361 A 19810812 Application: GB 79-44603 19791231.CAN 96:142862 AN 1982:142862.

[0563] Furthermore, N-protectedmethyl(5-amino-1,2,4-thiadiazol-3-yl)acetate was prepared as describedin Tet.Lett. 1993, 34(40), 6423-6426. This document describes thepreparation of a compound of formula (IV):

[0564] wherein:

[0565] either R′=H, X=H₂, and R=Me; or

[0566] R′=OMe, X=O, NOH or NOMe, and R=Me, Et, Bn or Ph.

[0567] After removal of the protecting group on the exocyclic aminogroup, the resulting products may be reacted e g as described in thesulfonamide couplings mentioned above.

[0568] The compound methyl(5-amino-1,3,4-thiadiazol-2-yl)acetate offormula (V):

[0569] was prepared as described in Bioorg.Med.Chem.Lett. 1996, 6(13),1487-1490. The compound of formula (VII) may be reacted e g as describedin the sulfonamide couplings mentioned above.

[0570] Various embodiments of the present invention have been describedabove but a person skilled in the art realizes further minor alterationswhich would fall into the scope of the present invention. The breadthand scope of the present invention should not be limited by any of theabove-described exemplary embodiments, but should be defined only inaccordance with the following claims and their equivalents.

What is claimed is:
 1. A compound of formula (I)

wherein: T is an aryl ring or heteroaryl ring, optionally independentlysubstituted by [R]_(n), wherein n is an integer 0-5, and R is hydrogen,aryl, heteroaryl, a heterocyclic ring, optionally halogenatedC₁₋₆-alkyl, optionally halogenated C₁₋₆-alkoxy, C₁₋₆-alkylsulfonyl,carboxy, cyano, nitro, halogen, amine which is mono- or di-substituted,amide which is optionally mono- or di-substituted, aryloxy,arylsulfonyl, arylamino, wherein aryl, heteroaryl and aryloxy residuesand heterocyclic rings are further optionally substituted in one or morepositions independently of each other by C₁₋₆-acyl, C₁₋₆-alkylthio,cyano, nitro, hydrogen, halogen, optionally halogenated C₁₋₆-alkyl,optionally halogenated C₁₋₆-alkoxy, amide which is optionally mono- ordi-substituted, (benzoylamino)methyl, carboxy, 2-thienylmethylamino or({[4-(2-ethoxy-2-oxoethyl)-1,3-thiazol-2-yl]amino}carbonyl); R¹ ishydrogen or C₁₋₆-alkyl; A₁ and A₂ are a nitrogen atom or C-Z, providedthat A₁ and A₂ have different meanings, wherein: Z is selected from anaryl ring or heteroaryl ring, which is further optionally substituted inone or more positions independently of each other by hydrogen,C₁₋₆-alkyl, halogenated C₁₋₆-alkyl, halogen, C₁₋₆-alkoxy, nitro,C₁₋₆-alkoxycarbonyl, C₁₋₆-alkylsulfonyl, acetylamino or aryloxy, whereinthe aryloxy is further optionally substituted in one or more positionsindependently of each other by hydrogen and halogen; or is X—Y—R²,wherein X is CH₂ or CO; Y is CH₂, CO or a single bond; R² is selectedfrom C₁₋₆-alkyl, azido, arylthio, heteroarylthio, halogen,hydroxymethyl, 2-hydroxyethylaminomethyl, methylsulfonyloxymethyl,3-oxo-4-morpholinolinylmethylene, C₁₋₆-alkoxycarbonyl,5-methyl-1,3,4-oxadiazol-2-yl; NR³R⁴, wherein R³ and R⁴ are eachindependently selected from hydrogen, C₁₋₆-alkyl, optionally halogenatedC₁₋₆-alkylsulfonyl, C₁₋₆-alkoxy, 2-methoxyethyl, 2-hydroxyethyl,1-methylimidazolylsulfonyl, C₁₋₆-acyl, cyclohexylmethyl,cyclopropanecarbonyl, aryl, optionally halogenated arylsulfonyl,furylcarbonyl, tetrahydro-2-furanylmethyl, N-carbethoxypiperidyl, orC₁₋₆-alkyl substituted with one or more aryl, heterocyclic orheteroaryl, or NR³R⁴ represent together heterocyclic systems which areimidazole, piperidine, pyrrolidine, piperazine, morpholine, oxazepine,oxazole, thiomorpholine, 1,1-dioxidothiomorpholine,2-(3,4-dihydro-2(1H)isoquinolinyl), or(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl, which heterocyclic systemsare optionally substituted by C₁₋₆-alkyl, C₁₋₆-acyl, hydroxy, oxo,t-butoxycarbonyl; OCONR³R⁴, wherein R³ and R⁴ are each independentlyselected from hydrogen, C₁₋₆-alkyl or form together with the N-atom towhich they are attached morpholinyl; R⁵O, wherein R⁵ is hydrogen,optionally halogenated C₁₋₆-alkyl, aryl, heteroaryl, C₁₋₆-acyl,C₁₋₆-alkylsulfonyl, arylcarbonyl, heteroarylcarbonyl,2-carbomethoxyphenyl; or a salt, hydrate or solvate thereof, with theproviso that when: A₁ is C-Z and A₂ is a nitrogen atom, then T is notphenyl only substituted with a nitrogen containing substituent inposition 4 with a nitrogen atom closest to the phenyl ring, is notphenyl only substituted with methyl in position 2, is not phenyl onlysubstituted with methyl in position 4, and is not phenyl onlysubstituted with ethyl in position 4; A₁ is a nitrogen atom and A₂ isC-Z, then Z is not 2-furyl, 5-nitro-2-furyl, 2-thienyl, optionallysubstituted phenyl, para-substituted benzyl; A₁ is a nitrogen atom andA₂ is C-Z, X is CH₂, Y is a single bond, then R² is not C₁₋₆-alkyl,methoxy, ethoxy, benzothiazol-2-ylthio and NR³R⁴, wherein R³ and R⁴ areselected from methyl, ethyl, n-propyl, n-butyl; A₁ is a nitrogen atomand A₂ is C-Z, X is CH₂, Y is CH₂, then R² is not C₁₋₆-alkyl and NR³R⁴,wherein R³ and R⁴ are selected from methyl, ethyl, n-propyl, n-butyl. 2.The compound according to claim 1, wherein T is selected from5-chloro-1,3-dimethyl-1H-pyrazol-4-yl; 4-chloro-2,3,1-benzoxadiazolyl;5-(dimethylamino)-1-naphthyl; 1-methylimidazol-4-yl; 1-naphthyl;2-naphthyl; 8-quinolinyl; thienyl substituted with one or more of(benzoylamino)methyl, bromo, chloro, 3-isoxazolyl,2-(methylsulfanyl)-4-pyrimidinyl,1-methyl-5-(trifluoromethyl)pyrazol-3-yl, phenylsulfonyl, pyridyl;phenyl substituted with one or more of acetylamino, 3-acetylaminophenyl,3-acetylphenyl, benzeneamino, 1,3-benzodioxol-5-yl, 2-benzofuryl,benzylamino, 3,5-bis(trifluoromethyl)phenyl, bromo, butoxy, carboxy,chloro, 4-carboxyphenyl, 3-chloro-2-cyanophenoxy, 4-chlorophenyl,5-chloro-2-thienyl, cyano, 3,4-dichlorophenyl,({[4-(2-ethoxy-2-oxoethyl)-1,3-thiazol-2-yl]amino}carbonyl), fluoro,5-fluoro-2-methoxyphenyl, 2-furyl, hydrogen, iodo, isopropyl,methanesulfonyl, methoxy, methyl, 4-methyl-i -piperazinyl,4-methyl-1-piperidinyl, 4-methylsulfanylphenyl, 5-methyl-2-thienyl,4-morpholinyl, nitro, 3-nitrophenyl, phenoxy, phenyl, n-propyl,4-pyridyl, 3-pyridylmethylamino, 1-pyrrolidinyl, 2-thienyl, 3-thienyl,2-thienylmethylamino, trifluoromethoxy, 4-trifluoromethoxyphenyl,trifluoromethyl; or R¹ is hydrogen or methyl; A₁ and A₂ are a nitrogenatom or C-Z, provided that A₁ and A₂ have different meanings, wherein: Zis selected from 1-benzothien-3-yl, 3-(2,5-dimethylfuryl), pyridinyl;thienyl optionally substituted with one or more of chloro,methylsulfonyl; phenyl optionally substituted with one or more ofethoxycarbonyl, nitro, fluoro, methyl, methoxy, acetylamino, chloro,4-chlorophenoxy, trifluoromethyl; or is X—Y—R², wherein X is CH₂ or CO;Y is CH₂, CO or a single bond; R² is selected from n-propyl, azido,bromo, chloro, 2-pyridinylsulfanyl, 3-oxo-4-morpholinolinylmethylene,ethoxycarbonyl, 5-methyl-1,3,4-oxadiazol-2-yl, hydroxymethyl,2-hydroxyethylaminomethyl, methylsulfonyloxymethyl; NR³R⁴, wherein R³and R⁴ are each independently selected from acetyl, benzhydryl,1,3-benzodioxol-5-ylmethyl, benzyl, 3-chloro-2-methylphenylsulfonyl,cyclohexyl, cyclohexylmethyl, cyclopropanecarbonyl, ethyl,2-furylcarbonyl, 2-furylmethyl, hydrogen, 2-hydroxyethyl,2-(1H-indol-3-yl)ethyl, isopropyl, methoxy, 2-methoxyethyl, methyl,4-(1-methylimidazolyl)sulfonyl, methylsulfonyl, phenyl,(1S)-phenylethyl, n-propyl, tetrahydro-2-furanylmethyl,trifluoromethylsulfonyl, N-carbethoxypiperidyl; or NR³R⁴ representtogether 4-acetylpiperazinyl, 4-t-butoxycarbonylpiperazinyl,2-(3,4-dihydro-2(1H)isoquinolinyl), (2R,6S)-2,6-dimethylmorpholinyl,(2R)-2,4-dimethyl-1-piperazinyl, 2-hydroxy-3-oxomorpholinyl, imidazolyl,2-methyl-3-oxomorpholinyl, 4-methyl-2-oxopiperazinyl,4-methylpiperazinyl, morpholinyl,(1S,4S)-2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl, 2-oxoimidazolinyl,3-oxomorpholinyl, 3-oxo-1,4-oxazepinyl, 2-oxooxazolinyl, piperazinyl;piperidinyl; pyrrolidinyl; pyrrolidonyl, thiomorpholinyl;1,1-dioxido-thiomorpholinyl; OCONR³R⁴, wherein R³ and R⁴ are eachindependently selected from ethyl, hydrogen or form together with theN-atom to which they are attached morpholinyl; R⁵O, wherein R⁵ isacetyl, benzoyl, benzyl, ethyl, 2-fluoroethyl, 2-furylcarbonyl,hydrogen, isobutyryl, isopropyl, methyl, 2-carbomethoxyphenyl,methylsulfonyl, phenyl, n-propionyl, 3-pyridinyl, 2,2,2-trifluoroethyl;with the proviso that when: A₁ is C-Z and A₂ is a nitrogen atom, then Tis not phenyl only substituted with nitro, 4-morpholinyl,1-pyrrolidinyl, acetylamino, benzeneamino, benzylamino,3-pyridylmethylamino, 4-methyl-1-piperazinyl, 4-methyl-1-piperidinyl, or2-thienylmethylamino in position 4, is not phenyl only substituted withmethyl in position 2, and is not phenyl only substituted with methyl inposition 4; A₁ is a nitrogen atom and A₂ is C-Z, then Z is not 2-thienyland phenyl optionally substituted with one or more of ethoxycarbonyl,nitro, fluoro, methyl, methoxy, acetylamino, chloro, 4-chlorophenoxy,trifluoromethyl; A₁ is a nitrogen atom and A₂ is C-Z, X is CH₂, Y is asingle bond, then R² is not n-propyl, methoxy, ethoxy and NR³R⁴, whereinR³ and R⁴ are selected from methyl, ethyl, n-propyl; A₁ is a nitrogenatom and A₂ is C-Z, X is CH₂, Y is CH₂, then R² is not n-propyl andNR³R⁴, wherein R³ and R⁴ are selected from methyl, ethyl, n-propyl. 3.The compound of claim 1 selected from the group consisting of:ethyl(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)acetate(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)aceticacid2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)-N-methylacetamide2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)-N-ethylacetamide2,5-dichloro-N-[5-(3-chlorothien-2-yl)-1,3,4-thiadiazol-2-yl]benzenesulfonamideisopropyl(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)acetate3-chloro-N-[5-(2-hydroxyethyl)-1,3,4-thiadiazol-2-yl]-2-methylbenzenesulfonamide3-chloro-N-[5-(2-ethoxyethyl)-1,3,4-thiadiazol-2-yl]-2-methylbenzenesulfonamide2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)-N,N-diethylacetamidemethyl(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)acetate3-chloro-N-[5-(2-isopropoxyethyl)-1,3,4-thiadiazol-2-yl]-2-methylbenzenesulfonamide3-chloro-N-[5-(2-methoxyethyl)-1,3,4-thiadiazol-2-yl]-2-methylbenzenesulfonamide2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)ethylmethanesulfonate2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)acetamide3-chloro-N-{5-[2-(2-fluoroethoxy)ethyl]-1,3,4-thiadiazol-2-yl}-2-methylbenzenesulfonamide3-chloro-2-methyl-N-{5-[2-(2,2,2-trifluoroethoxy)ethyl]-1,3,4-thiadiazol-2-yl}benzenesulfonamide2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)ethylacetate3-chloro-2-methyl-N-[5-(2-morpholin-4-ylethyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamideN-[5-(2-bromoethyl)-1,3,4-thiadiazol-2-yl]-3-chloro-2-methylbenzenesulfonamide2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)ethylmorpholine-4-carboxylate2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)ethyldiethylcarbamate2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)ethylpropionate2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)ethyl2-methylpropanoate2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)ethyl2-furoate2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)ethylbenzoate2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)-N-methoxy-N-methylacetamide2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)ethylethylcarbamateN-[2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)ethyl]-N-ethylacetamide3-chloro-2-methyl-N-[5-(2-oxopentyl)-1,3,⁴-thiadiazol-2-yl]benzenesulfonamideN-{5-[2-(1,1-dioxidothiomorpholin-4-yl)-2-oxoethyl]-1,3,4-thiadiazol-2-yl}-4-propylbenzenesulfonamide2,4,6-trichloro-N-[5-(2-morpholin-4-ylethyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide2,4-dichloro-N-[5-(2-morpholin-4-ylethyl)-1,3,⁴-thiadiazol-2-yl]benzenesulfonamide3-chloro-2-methyl-N-{5-[2-(3-oxomorpholin-4-yl)ethyl]-1,3,4-thiadiazol-2-yl}benzenesulfonamide2,4-dichloro-6-methyl-N-[5-(2-morpholin-4-ylethyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamideN-[5-(2-morpholin-4-ylethyl)-1,3,4-thiadiazol-2-yl]-4-propylbenzenesulfonamide2,4-dichloro-6-methyl-N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide2,4,6-trichloro-N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamideN-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2-yl]-1,1′-biphenyl-4-sulfonamideN-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2-yl]-4-propylbenzenesulfonamideN-[5-(2-oxo-2-thiomorpholin-4-ylethyl)-1,3,4-thiadiazol-2-yl]-1,1′-biphenyl-4-sulfonamideN-[5-(2-oxo-2-thiomorpholin-4-ylethyl)-1,3,4-thiadiazol-2-yl]-4-propylbenzenesulfonamide2,4-dichloro-6-methyl-N-[5-(2-oxo-2-thiomorpholin-4-ylethyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamideN-[5-(2-oxo-2-piperidin-1-ylethyl)-1,3,4-thiadiazol-2-yl]-1,1′-biphenyl-4-sulfonamideN-[5-(2-oxo-2-piperidin-1-ylethyl)-1,3,4-thiadiazol-2-yl]-4-propylbenzenesulfonamide2,4-dichloro-6-methyl-N-[5-(2-oxo-2-piperidin-1-ylethyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide2,4,6-trichloro-N-[5-(2-oxo-2-piperidin-1-ylethyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamideethyl(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)(oxo)acetate2-{5-[(1,1′-biphenyl-4-ylsulfonyl)amino]-1,3,4-thiadiazol-2-yl}-N-ethyl-N-methylacetamideN-ethyl-N-methyl-2-(5-{[(4-propylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)acetamide2-(5-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)-N-ethyl-N-methylacetamideN-ethyl-N-methyl-2-(5-{[(2,4,6-trichlorophenyl)sulfonyl]amino}-1,3,4-thiadiazo1-2-yl)acetamide2,4,6-trichloro-N-[5-(2-oxo-2-thiomorpholin-4-ylethyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide2-{5-[(1,1′-biphenyl-4-ylsulfonyl)amino]-1,3,4-thiadiazol-2-yl}-N-isopropyl-N-methylacetamide2-{5-[(1,1′-biphenyl-4-ylsulfonyl)amino]-1,3,4-thiadiazol-2-yl}-N,N-diethylacetamideN,N-diethyl-2-(5-{[(4-propylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)acetamide2-(5-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)-N,N-diethylacetamideN,N-diethyl-2-(5-{[(2,4,6-trichlorophenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)acetamide2-{5-[(1,1′-biphenyl-4-ylsulfonyl)amino]-1,3,4-thiadiazol-2-yl}-N,N-diisopropylacetamideN,N-diisopropyl-2-(5-{[(4-propylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)acetamide2-(5-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)-N,N-diisopropylacetamideN,N-diisopropyl-2-(5-{[(2,4,6-trichlorophenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)acetamide4-propyl-N-(5-pyridin-3-yl-1,3,4-thiadiazol-2-yl)benzenesulfonamide3-chloro-N-[5-(5-chlorothien-2-yl)-1,3,4-thiadiazol-2-yl]-2-methylbenzenesulfonamide2,4,6-trichloro-N-(5-pyridin-3-yl-1,3,4-thiadiazol-2-yl)benzenesulfonamide2,4,6-trichloro-N-[5-(5-chlorothien-2-yl)-1,3,4-thiadiazol-2-yl]benzenesulfonamideN-(5-pyridin-3-yl-1,3,4-thiadiazol-2-yl)-1,1′-biphenyl-4-sulfonamide2,4-dichloro-6-methyl-N-(5-pyridin-3-yl-1,3,4-thiadiazol-2-yl)benzenesulfonamide2,4-dichloro-N-[5-(5-chlorothien-2-yl)-1,3,4-thiadiazol-2-yl]-6-methylbenzenesulfonamide2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)-N,N-dipropylacetamide3-chloro-2-methyl-N-[5-(2-oxo-2-piperazin-1-ylethyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide2,4-dichloro-N-[5-(2,5-dimethyl-3-furyl)-1,3,4-thiadiazol-2-yl]-6-methylbenzenesulfonamideN-[5-(3-chlorothien-2-yl)-1,3,4-thiadiazol-2-yl]-4-propylbenzenesulfonamide3-chloro-N-[5-(3-chlorothien-2-yl)-1,3,4-thiadiazol-2-yl]-2-methylbenzenesulfonamide2,4,6-trichloro-N-[5-(3-chlorothien-2-yl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide2,4-dichloro-N-[5-(3-chlorothien-2-yl)-1,3,4-thiadiazol-2-yl]-6-methylbenzenesulfonamide4-bromo-2-methyl-N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamideN-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2-yl]-2,4-bis(trifluoromethyl)benzenesulfonamide2-methyl-N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2-yl]-4-(trifluoromethoxy)benzenesulfonamideN-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2-yl]-4-phenoxybenzenesulfonamide4-chloro-2,6-dimethyl-N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide2,4-dichloro-N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamidetert-butyl4-[(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)acetyl]piperazine-1-carboxylate2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)-N,N-dimethylacetamide3-chloro-2-methyl-N-{5-[2-(pyridin-3-yloxy)ethyl]-1,3,4-thiadiazol-2-yl}benzenesulfonamide2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)-N-isopropyl-N-methylacetamide2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)-N-ethyl-methylacetamide3-chloro-2-methyl-N-[5-(2-oxo-2-thiomorpholin-4-ylethyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide3-chloro-2-methyl-N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)-N,N-diisopropylacetamide3-chloro-2-methyl-N-[5-(2-oxo-2-pyrrolidin-1-ylethyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide3-chloro-2-methyl-N-[5-(2-oxo-2-piperidin-1-ylethyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide3-chloro-2-methyl-N-[5-(morpholin-4-ylmethyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide3-chloro-N-{5-[2-(1H-imidazol-1-yl)ethyl]-1,3,4-thiadiazol-2-yl}-2-methylbenzenesulfonamide2,4,5-trichloro-N-[5-(3-chlorothien-2-yl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide2,3,4-trichloro-N-[5-(3-chlorothien-2-yl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide4-bromo-N-[5-(3-chlorothien-2-yl)-1,3,4-thiadiazol-2-yl]-2,5-difluorobenzenesulfonamide4-bromo-5-chloro-N-[5-(3-chlorothien-2-yl)-1,3,4-thiadiazol-2-yl]thiophene-2-sulfonamide2,6-dichloro-N-[5-(3-chlorothien-2-yl)-1,3,4-thiadiazol-2-yl]benzenesulfonamideN-[2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)ethyl]acetamide3-chloro-2-methyl-N-(5-{2-[(methylsulfonyl)amino]ethyl}-1,3,4-thiadiazol-2-yl)benzenesulfonamide3-chloro-2-methyl-N-{5-[2-(3-oxo-1,4-oxazepan-4-yl)ethyl]-1,3,4-thiadiazol-yl}benzenesulfonamide3-chloro-2-methyl-N-{5-[2-(2-oxopyrrolidin-1-yl)ethyl]-1,3,4-thiadiazol-2-yl}benzenesulfonamide3-chloro-2-methyl-N-(5-{2-[methyl(methylsulfonyl)amino]ethyl}-1,3,4-thiadiazol-2-yl)benzenesulfonamideN-[2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)ethyl]-N-methylcyclopropanecarboxamide3-chloro-2-methyl-N-{5-[2-(4-methyl-2-oxopiperazin-1-yl)ethyl]-1,3,4-thiadiazol-2-yl}benzenesulfonamide3-chloro-2-methyl-N-[5-(2-{[(trifluoromethyl)sulfonyl]amino}ethyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide2,4-dichloro-N-{5-[2-(3-oxomorpholin-4-yl)ethyl]-1,3,4-thiadiazol-2-yl}benzenesulfonamide2,4-dichloro-6-methyl-N-{5-[2-(3-oxomorpholin-4-yl)ethyl]-1,3,4-thiadiazol-2-yl}benzenesulfonamide2,4,6-trichloro-N-{5-[2-(3-oxomorpholin-4-yl)ethyl]-1,3,4-thiadiazol-2-yl}benzenesulfonamide4-(2-furyl)-N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide5′-fluoro-2′-methoxy-N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2-yl]-1,1′-biphenyl-4-sulfonamide4-(5-methylthien-2-yl)-N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide3′-acetyl-N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2-yl]-1,1′-biphenyl-4-sulfonamideN-[5-(2-motpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2-yl]-4′-(trifluoromethoxy)-1,1′-biphenyl-4-sulfonamide3′,4′-dichloro-N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2-yl]-1,1′-biphenyl-4-sulfonamide4-(1,3-benzodioxol-5-yl)-N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide4-(5-chlorothien-2-yl)-N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamideN-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2-yl]-4-pyridin-4-ylbenzenesulfonamideN-[4′-({[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2-yl]amino}sulfonyl)-1,1′-biphenyl-3-yl]acetamideN-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2-yl]-4-thien-3-ylbenzenesulfonamideN-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2-yl]-4-thien-2-ylbenzenesulfonamide4′-(methylthio)-N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2-yl]-1,1′-biphenyl-4-sulfonamideN-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2-yl]-3′,5′-bis(trifluoromethyl)-1,1′-biphenyl-4-sulfonamide4′-chloro-N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2-yl]-1,1′-biphenyl-4-sulfonamideN-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2-yl]-3′-nitro-1,1′-biphenyl-4-sulfonamide3-chloro-2-methyl-N-[5-(2-{methyl[(trifluoromethyl)sulfonyl]amino}ethyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamideN-[2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)ethyl]-1-methyl-1H-imidazole-4-sulfonamide3-chloro-N-{5-[2-(2-hydroxy-3-oxomorpholin-4-yl)ethyl]-1,3,4-thiadiazol-2-yl}-2-methylbenzenesulfonamide4,5-dichloro-N-{5-[2-(3-oxomorpholin-4-yl)ethyl]-1,3,4-thiadiazol-2-yl}thiophene-2-sulfonamideN-{5-[2-(3-oxomorpholin-4-yl)ethyl]-1,3,4-thiadiazol-2-yl}-4-phenoxybenzenesulfonamide3-fluoro-N-{5-[2-(3-oxomorpholin-4-yl)ethyl]-1,3,4-thiadiazol-2-yl}benzenesulfonamideN-{5-[2-(3-oxomorpholin-4-yl)ethyl]-1,3,4-thiadiazol-2-yl}-5-pyridin-2-ylthiophene-2-sulfonamideN-{2-chloro-4-[({5-[2-(3-oxomorpholin-4-yl)ethyl]-1,3,4-thiadiazol-2-yl}amino)sulfonyl]phenyl}acetamideethyl(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)acetate(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)aceticacid2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)-N-methylacetamide2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)-N-ethylacetamide2,5-dichloro-N-[3-(3-chlorothien-2-yl)-1,2,4-thiadiazol-5-yl]benzenesulfonamideisopropyl(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)acetate3-chloro-N-[3-(2-hydroxyethyl)-1,2,4-thiadiazol-5-yl]-2-methylbenzenesulfonamide3-chloro-N-[3-(2-ethoxyethyl)-1,2,4-thiadiazol-5-yl]-2-methylbenzenesulfonamide2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)-N,N-diethylacetamidemethyl(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)acetate3-chloro-N-[3-(2-isopropoxyethyl)-1,2,4-thiadiazol-5-yl]-2-methylbenzenesulfonamide3-chloro-N-[3-(2-methoxyethyl)-1,2,4-thiadiazol-5-yl]-2-methylbenzenesulfonamide2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)ethylmethanesulfonate2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)acetamide3-chloro-N-{3-[2-(2-fluoroethoxy)ethyl]-1,2,4-thiadiazol-5-yl}-2-methylbenzenesulfonamide3-chloro-2-methyl-N-{3-[2-(2,2,2-trifluoroethoxy)ethyl]-1,2,4-thiadiazol-5-yl}benzenesulfonamide2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)ethylacetate3-chloro-2-methyl-N-[3-(2-morpholin-4-ylethyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamideN-[3-(2-bromoethyl)-1,2,4-thiadiazol-5-yl]-3-chloro-2-methylbenzenesulfonamide2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)ethylmorpholine-4-carboxylate2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)ethyldiethylcarbamate2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)ethylpropionate2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)ethyl2-methylpropanoate2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)ethyl2-furoate2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)ethylbenzoate2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)-N-methoxy-N-methylacetamide3-chloro-N-{3-[2-(diethylamino)ethyl]-1,2,4-thiadiazol-5-yl}-2-methylbenzenesulfonamide2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)ethylethylcarbamateN-[2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)ethyl]-N-ethylacetamide3-chloro-2-methyl-N-[3-(2-oxopentyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamideN-{3-[2-(1,1-dioxidothiomorpholin-4-yl)-2-oxoethyl]-1,2,4-thiadiazol-5-yl}-4-propylbenzenesulfonamide2,4,6-trichloro-N-[3-(2-morpholin-4-ylethyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide2,4-dichloro-N-[3-(2-morpholin-4-ylethyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide3-chloro-2-methyl-N-{3-[2-(3-oxomorpholin-4-yl)ethyl]-1,2,4-thiadiazol-5-yl}benzenesulfonamide2,4-dichloro-6-methyl-N-[3-(2-morpholin-4-ylethyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamideN-[3-(2-morpholin-4-ylethyl)-1,2,4-thiadiazol-5-yl]-4-propylbenzenesulfonamide2,4-dichloro-6-methyl-N-[3-(2-morpholin-4-yl-2-oxoethyl)l1,2,4-thiadiazol-5-yl]benzenesulfonamide2,4,6-trichloro-N-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamideN-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5-yl]-1,1′-biphenyl-4-sulfonamideN-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5-yl]-4-propylbenzenesulfonamideN-[3-(2-oxo-2-thiomorpholin-4-ylethyl)-1,2,4-thiadiazol-5-yl]-1,1′-biphenyl-4-sulfonamideN-[3-(2-oxo-2-thiomorpholin-4-ylethyl)-1,2,4-thiadiazol-5-yl]-4-propylbenzenesulfonamide2,4-dichloro-6-methyl-N-[3-(2-oxo-2-thiomorpholin-4-ylethyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamideN-[3-(2-oxo-2-piperidin-1-ylethyl)-1,2,4-thiadiazol-5-yl]-1,1′-biphenyl-4-sulfonamideN-[3-(2-oxo-2-piperidin-1-ylethyl)-1,2,4-thiadiazol-5-yl]-1,1′-biphenyl-4-propylbenzenesulfonamide2,4-dichloro-6-methyl-N-[3-(2-oxo-2-piperidin-1-ylethyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide2,4,6-trichloro-N-[3-(2-oxo-2-piperidin-1-ylethyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamideN-(3-phenyl-1,2,4-thiadiazol-5-yl)-4-propylbenzenesulfonamideethyl(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)(oxo)acetate3-chloro-2-methyl-N-(3-phenyl-1,2,4-thiadiazol-5-yl)benzenesulfonamide3-chloro-N-[3-(4-fluoro-3-methylphenyl)-1,2,4-thiadiazol-5-yl]-2-methylbenzenesulfonamide2,4,6-trichloro-N-(3-phenyl-1,2,4-thiadiazol-5-yl)benzenesulfonamideN-(3-phenyl-1,2,4-thiadiazol-5-yl)-1,1′-biphenyl-4-sulfonamide2,4-dichloro-6-methyl-N-(3-phenyl-1,2,4-thiadiazol-5-yl)benzenesulfonamide2-{5-[(1,1′-biphenyl-4-ylsulfonyl)amino]-1,2,4-thiadiazol-3-yl}-N-ethyl-N-methylacetamideN-ethyl-N-methyl-2-(5-{[(4-propylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)acetamide2-(5-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)-N-ethyl-N-methylacetamideN-ethyl-N-methyl-2-(5-{[(2,4,6-trichlorophenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)acetamide2,4,6-trichloro-N-[3-(2-oxo-2-thiomorpholin-4-ylethyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide2-{5-[(1,1′-biphenyl-4-ylsulfonyl)amino]-1,2,4-thiadiazol-3-yl}-N-isopropyl-N-methylacetamide2-{5-[(1,1′-biphenyl-4-ylsulfonyl)amino]-1,2,4-thiadiazol-3-yl}-N,N-diethylacetamideN,N-diethyl-2-(5-{[(4-propylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)acetamide2-(5-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)-N,N-diethylacetamideN,N-diethyl-2-(5-{[(2,4,6-trichlorophenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)acetamide2-{5-[(1,1′-biphenyl-4-ylsulfonyl)amino]-1,2,4-thiadiazol-3-yl}-N,N-diisopropylacetamideN,N-diisopropyl-2-(5-{[(4-propylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)acetamide2-(5-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)-N,N-diisopropylacetamideN,N-diisopropyl-2-(5-{[(2,4,6-trichlorophenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)acetamideN-[4-(5-{[(4-propylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)phenyl]acetamide4-propyl-N-(3-pyridin-3-yl-1,2,4-thiadiazol-5-yl)benzenesulfonamideN-[3-(2-chloro-5-nitrophenyl)-1,2,4-thiadiazol-5-yl]-4-propylbenzenesulfonamideN-[3-(2-chlorophenyl)-1,2,4-thiadiazol-5-yl]-4-propylbenzenesulfonamide3-chloro-N-[3-(2-chloro-5-nitrophenyl)-1,2,4-thiadiazol-5-yl]-2-methylbenzenesulfonamide3-chloro-N-[3-(5-chlorothien-2-yl)-1,2,4-thiadiazol-5-yl]-2-methylbenzenesulfonamide3-chloro-N-[3-(2-chlorophenyl)-1,2,4-thiadiazol-5-yl]-2-methylbenzenesulfonamideN-[4-(5-{[(2,4,6-trichlorophenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)phenyl]acetamide2,4,6-trichloro-N-(3-pyridin-3-yl-1,2,4-thiadiazol-5-yl)benzenesulfonamide2,4,6-trichloro-N-[3-(2-chloro-5-nitrophenyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide2,4,6-trichloro-N-[3-(5-chlorothien-2-yl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide2,4,6-trichloro-N-[3-(2-chlorophenyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamideN-(4-{5-[(1,1′-biphenyl-4-ylsulfonyl)amino]-1,2,4-thiadiazol-3-yl}phenyl)acetamideN-(3-pyridin-3-yl-1,2,4-thiadiazol-5-yl)-1,1′-biphenyl-4-sulfonamideN-[3-(2-chloro-5-nitrophenyl)-1,2,4-thiadiazol-5-yl]-1,1′-biphenyl-4-sulfonamideN-[3-(2-chlorophenyl)-1,2,4-thiadiazol-5-yl]1,1′-biphenyl-4-sulfonamideN-[4-(5-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)phenyl]acetamide2,4-dichloro-6-methyl-N-(3-pyridin-3-yl-1,2,4-thiadiazol-5-yl)benzenesulfonamide2,4-dichloro-N-[3-(2-chloro-5-nitrophenyl)-1,2,4-thiadiazol-5-yl]-6-methylbenzenesulfonamide2,4-dichloro-N-[3-(5-chlorothien-2-yl)-1,2,4-thiadiazol-5-yl]-6-methylbenzenesulfonamide2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)-N,N-dipropylacetamide3-chloro-2-methyl-N-[3-(2-oxo-2-piperazin-1-ylethyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide2,4-dichloro-N-[3-(2,5-dimethyl-3-furyl)-1,2,4-thiadiazol-5-yl]-6-methylbenzenesulfonamideN-[3-(3-chlorothien-2-yl)-1,2,4-thiadiazol-5-yl]-4-propylbenzenesulfonamide3-chloro-N-[3-(3-chlorothien-2-yl)-1,2,4-thiadiazol-5-yl]-2-methylbenzenesulfonamide2,4,6-trichloro-N-[3-(3-chlorothien-2-yl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide2,4-dichloro-N-[3-chlorothien-2-yl)-1,2,4-thiadiazol-5-yl]-6-methylbenzenesulfonamide2,4-dichloro-N-[3-(2-chlorophenyl)-1,2,4-thiadiazol-5-yl]-6-methylbenzenesulfonamide4-bromo-2-methyl-N-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamideN-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5-yl]-2,4-bis(trifluoromethyl)benzenesulfonamide2-methyl-N-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5-yl]-4-(trifluoromethoxy)benzenesulfonamideN-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5-yl]-4-phenoxybenzenesulfonamide4-chloro-2,6-dimethyl-N-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide2,4-dichloro-N-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamidetert-butyl4-[(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)acetyl]piperazine-1-carboxylate2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)-N,N-dimethylacetamide3-chloro-2-methyl-N-{3-[2-(pyridin-3-yloxy)ethyl]-1,2,4-thiadiazol-5-yl}benzenesulfonamide2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)-N-isopropyl-N-methylacetamide2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)-N-ethyl-N-methylacetamide3-chloro-2-methyl-N-[3-(2-oxo-2-thiomorpholin-4-ylethyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide3-chloro-2-methyl-N-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)-N,N-diisopropylacetamide3-chloro-2-methyl-N-[3-(2-oxo-2-pyrrolidin-1-ylethyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide3-chloro-2-methyl-N-[3-(2-oxo-2-pyrrolidin-1-ylethyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide3-chloro-2-methyl-N-[3-(morpholin-4-ylmethyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide3-chloro-N-{3-[2-(1H-imidazol-1-yl)ethyl]-1,2,4-thiadiazol-5-yl}-2-methylbenzenesulfonamide2,4,5-trichloro-N-[3-(3-chlorothien-2-yl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide2,3,4-trichloro-N-[3-(3-chlorothien-2-yl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide2,3,4-trichloro-N-[3-(2-chlorophenyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamideN-[4-(5-{[(4-bromo-2,5-difluorophenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)phenyl]acetamide4-bromo-N-[3-(3-chlorothien-2-yl)-1,2,4-thiadiazol-5-yl]-2,5-difluorobenzenesulfonamide4,5-dichloro-N-[3-(2-chlorophenyl)-1,2,4-thiadiazol-5-yl]thiophene-2-sulfonamideN-[4-(5-{[(2,4,5-trichlorophenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)phenyl]acetamide4-bromo-5-chloro-N-[3-(3-chlorothien-2-yl)-1,2,4-thiadiazol-5-yl]thiophene-2-sulfonamide3-bromo-5-chloro-N-[3-(2-chlorophenyl)-1,2,4-thiadiazol-5-yl]thiophene-2-sulfonamideN-[4-(5-{[(2,6-dichlorophenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)phenyl]acetamide2,6-dichloro-N-[3-(3-chlorothien-2-yl)-1,2,4-thiadiazol-5-yl]benzenesulfonamideN-[2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)ethyl]acetamide3-chloro-2-methyl-N-(3-{2-[(methylsulfonyl)amino]ethyl}-1,2,4-thiadiazol-5-yl)benzenesulfonamide3-chloro-2-methyl-N-(3-{2-[(methylsulfonyl)amino]ethyl}-1,2,4-thiadiazol-5-yl}benzenesulfonamide3-chloro-2-methyl-N-{3-[2-(3-oxo-1,4-oxazepan-4-yl)ethyl]-1,2,4-thiadiazol-5-yl}benzenesulfonamide2,3,4-trichloro-N-{3-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1,2,4-thiadiazol-5-yl}benzenesulfonamideN-[3-(2-chloro-6-fluorophenyl)-1,2,4-thiadiazol-5-yl]-4-propylbenzenesulfonamide4-bromo-N-{3-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1,2,4-thiadiazol-5-yl}-2,5-difluorobenzenesulfonamide4,5-dichloro-N-[3-(2-chloro-6-fluorophenyl)-1,2,4-thiadiazol-5-yl]thiophene-2-sulfonamide4-bromo-5-chloro-N-{3-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1,2,4-thiadiazol-5-yl}thiophene-2-sulfonamide2,4-dichloro-N-[3-(2-chloro-6-fluorophenyl)-1,2,4-thiadiazol-5-yl]-6-methylbenzenesulfonamide4-bromo-N-[3-(2-chloro-6-fluorophenyl)-1,2,4-thiadiazol-5-yl]-2-methylbenzenesulfonamide3-chloro-2-methyl-N-(3-{2-[methyl(methylsulfonyl)amino]ethyl}-1,2,4-thiadiazol-5-yl)benzenesulfonamideN-[2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)ethyl]-N-methylcyclopropanecarboxamide3-chloro-2-methyl-N-{3-[2-(4-methyl-2-oxopiperazin-1-yl)ethyl]-1,2,4-thiadiazol-5-yl}benzenesulfonamide3-chloro-2-methyl-N-[3-(2-{[(trifluoromethyl)sulfonyl]amino}ethyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamideN-[4-(5-{[(4-bromo-5-chlorothien-2-yl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)phenyl]acetamide2,4-dichloro-N-{3-[2-(3-oxomorpholin-4-yl)ethyl]-1,2,4-thiadiazol-5-yl}benzenesulfonamide2,4-dichloro-6-methyl-N-{3-[2-(3-oxomorpholin-4-yl)ethyl]-1,2,4-thiadiazol-5-yl}benzenesulfonamide2,4,6-trichloro-N-{3-[2-(3-oxomorpholin-4-yl)ethyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide4-(2-furyl)-N-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide5′-fluoro-2′-methoxy-N-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5-yl]-1,1′-biphenyl-4-sulfonamide4-(5-methylthien-2-yl)-N-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide3′-acetyl-N-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5-yl]-1,1′-biphenyl-4-sulfonamideN-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5-yl]-4′-(trifluoromethoxy)-1,1-biphenyl-4-sulfonamide3′,4′-dichloro-N-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5-yl]-1,1′-biphenyl-4-sulfonamide4-(1,3-benzodioxol-5-yl)-N-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide4-(5-chlorothien-2-yl)-N-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamideN-[3-(2-motpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5-yl]-4-pyridin-4-ylbenzenesulfonamideN-[4′-({[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5-yl]amino}sulfonyl)-1,1′-biphenyl-3-yl]acetamideN-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5-yl]-4-thien-3-ylbenzenesulfonamideN-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5-yl]-4-thien-2-ylbenzenesulfonamide4′-(methylthio)-N-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5-yl]-1,1′-biphenyl-4-sulfonamideN-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5-yl]-3′,5′-bis(trifluoromethyl)-1,1′-biphenyl-4-sulfonamide4′-chloro-N-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5-yl]-1,1′-biphenyl-4-sulfonamideN-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5-yl]-3′-nitro-1,1′-biphenyl-4-sulfonamide3-chloro-2-methyl-N-[3-(2-{methyl[(trifluoromethyl)sulfonyl]amino}ethyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamideN-[2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)ethyl]-1-methyl-1H-imidazole-4-sulfonamide3-chloro-N-{3-[2-(2-hydroxy-3-oxomorpholin-4-yl)ethyl]-1,2,4-thiadiazol-5-yl}-2-methylbenzenesulfonamide4,5-dichloro-N-{3-[2-(3-oxomorpholin-4-yl)ethyl]-1,2,4-thiadiazol-5-yl}thiophene-2-sulfonamideN-{3-[2-(3-oxomorpholin-4-yl)ethyl]-1,2,4-thiadiazol-5-yl}-4-phenoxybenzenesulfonamide3-fluoro-N-{3-[2-(3-oxomorpholin-4-yl)ethyl]-1,2,4-thiadiazol-5-yl}benzenesulfonamideN-{3-[2-(3-oxomorpholin-4-yl)ethyl]-1,2,4-thiadiazol-5-yl}-5-pyridin-2-ylthiophene-2-sulfonamideN-{2-chloro-4-[({3-[2-(3-oxomorpholin-4-yl)ethyl]-1,2,4-thiadiazol-5-yl}amino)sulfonyl]phenyl}acetamide.4. The compound of claim 1 having formula (II):

wherein T, R¹ and Z are as defined in claim
 1. 5. The compound of claim1 having formula (III):

wherein T, R¹ and Z are as defined in claim
 1. 6. A pharmaceuticalcomposition comprising a compound of formula (I) as defined in claim 1and a pharmaceutically acceptable carrier.
 7. A method for the treatmentor prevention of diabetes, syndrome X, obesity, glaucoma,hyperlipidemia, hyperglycemia, hyperinsulinemia, hypertension,osteoporosis, dementia, depression, virus diseases or inflammatorydisorders without causing hypoglycemia and to achieve immuno-modulation,said method comprising administering to a mammal in need of suchtreatment an effective amount of a compound of formula (I)

wherein T is an aryl ring or heteroaryl ring, optionally independentlysubstituted by [R]_(n), wherein n is an integer 0-5, and R is hydrogen,aryl, heteroaryl, a heterocyclic ring, optionally halogenatedC₁₋₆-alkyl, optionally halogenated C₁₋₆-alkoxy, C₁₋₆-alkylsulfonyl,carboxy, cyano, nitro, halogen, amine which is optionally mono- ordi-substituted, amide which is optionally mono- or di-substituted,aryloxy, arylsulfonyl, arylamino, wherein aryl, heteroaryl and aryloxyresidues and heterocyclic rings are further optionally substituted inone or more positions independently of each other by C₁₋₆-acyl,C₁₋₆-alkylthio, cyano, nitro, hydrogen, halogen, optionally halogenatedC₁₋₆-alkyl, optionally halogenated C₁₋₆-alkoxy, amide which isoptionally mono- or di-substituted, (benzoylamino)methyl, carboxy,2-thienylmethylamino or({[4-(2-ethoxy-2-oxoethyl)-1,3-thiazol-2-yl]amino}carbonyl); R¹ ishydrogen or C₁₋₆-alkyl; A₁ and A₂ are a nitrogen atom or C-Z, providedthat A₁ and A₂ have different meanings, wherein: Z is selected from anaryl ring or heteroaryl ring, which is further optionally substituted inone or more positions independently of each other by hydrogen,C₁₋₆-alkyl, halogenated C₁₋₆-alkyl, halogen, C₁₋₆-alkoxy, nitro,C₁₋₆-alkoxycarbonyl, C₁₋₆-alkylsulfonyl, acetylamino or aryloxy, whereinthe aryloxy is further optionally substituted in one or more positionsindependently of each other by hydrogen and halogen; or is X—Y—R²,wherein X is CH₂or CO; Y is CH₂, CO or a single bond; R² is selectedfrom C₁₋₆-alkyl, azido, arylthio, heteroarylthio, halogen,hydroxymethyl, 2-hydroxyethylaminomethyl, methylsulfonyloxymethyl,3-oxo-4-morpholinolinylmethylene, C₁₋₆-alkoxycarbonyl,5-methyl-1,3,4-oxadiazol-2-yl; NR³R⁴, wherein R³ and R⁴ are eachindependently selected from hydrogen, C₁₋₆-alkyl, optionally halogenatedC₁₋₆-alkylsulfonyl, C₁₋₆-alkoxy, 2-methoxyethyl, 2-hydroxyethyl,1-methylimidazolylsulfonyl, C₁₋₆-acyl, cyclohexylmethyl,cyclopropanecarbonyl, aryl, optionally halogenated arylsulfonyl,furylcarbonyl, tetrahydro-2-furanylmethyl, N-carbethoxypiperidyl, orC₁₋₆-alkyl substituted with one or more aryl, heterocyclic orheteroaryl, or NR³R⁴ represent together heterocyclic systems which areimidazole, piperidine, pyrrolidine, piperazine, morpholine, oxazepine,oxazole, thiomorpholine, 1,1-dioxidothiomorpholine,2-(3,4-dihydro-2(1H)isoquinolinyl), or(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl, which heterocyclic systemsare optionally substituted by C₁₋₆-alkyl, C₁₋₆-acyl, hydroxy, oxo,t-butoxycarbonyl; OCONR³R⁴, wherein R³ and R⁴ are each independentlyselected from hydrogen, C₁₋₆-alkyl or form together with the N-atom towhich they are attached morpholinyl; R⁵O, wherein R⁵ is hydrogen,optionally halogenated C₁₋₆-alkyl, aryl, heteroaryl, C₁₋₆-acyl,C₁₋₆-alkylsulfonyl, arylcarbonyl, heteroarylcarbonyl,2-carbomethoxyphenyl; or a salt, hydrate or solvate thereof.
 8. Themethod according to claim 7, wherein the immuno-modulation is selectedfrom tuberculosis, lepra, and psoriasis.
 9. The method according toclaim 7, wherein T is selected from5-chloro-1,3-dimethyl-1H-pyrazol-4-yl; 4-chloro-2,3,1-benzoxadiazolyl;5-(dimethylamino)-1-naphthyl; 1-methylimidazol-4-yl; 1-naphthyl;2-naphthyl; 8-quinolinyl; thienyl substituted with one or more of(benzoylamino)methyl, bromo, chloro, 3-isoxazolyl,2-(methylsulfanyl)-4-pyrimidinyl,1-methyl-5-(trifluoromethyl)pyrazol-3-yl, phenylsulfonyl, pyridyl;phenyl substituted with one or more of acetylamino, 3-acetylaminophenyl,3-acetylphenyl, benzeneamino, 1,3-benzodioxol-5-yl, 2-benzofuryl,benzylamino, 3,5-bis(trifluoromethyl)phenyl, bromo, butoxy, carboxy,chloro, 4-carboxyphenyl, 3-chloro-2-cyanophenoxy, 4-chlorophenyl,5-chloro-2-thienyl, cyano, 3,4-dichlorophenyl,({[4-(2-ethoxy-2-oxoethyl)-1,3-thiazol-2-yl]amino}carbonyl), fluoro,5-fluoro-2-methoxyphenyl, 2-furyl, hydrogen, iodo, isopropyl,methanesulfonyl, methoxy, methyl, 4-methyl-1-piperazinyl,4-methyl-1-piperidinyl, 4-methylsulfanylphenyl, 5-methyl-2-thienyl,4-morpholinyl, nitro, 3-nitrophenyl, phenoxy, phenyl, n-propyl,4-pyridyl, 3-pyridylmethylamino, 1-pyrrolidinyl, 2-thienyl, 3-thienyl,2-thienylmethylamino, trifluoromethoxy, 4-trifluoromethoxyphenyl,trifluoromethyl; or R¹ is hydrogen or methyl; A₁ and A₂ are a nitrogenatom or C-Z, provided that Al and A₂ have different meanings, wherein: Zis selected from 1-benzothien-3-yl, 3-(2,5-dimethylfuryl), pyridinyl;thienyl optionally substituted with one or more of chloro,methylsulfonyl; phenyl optionally substituted with one or more ofethoxycarbonyl, nitro, fluoro, methyl, methoxy, acetylamino, chloro,4-chlorophenoxy, trifluoromethyl; or is X—Y—R², wherein X is CH₂ or CO;Y is CH₂, CO or a single bond; R² is selected from n-propyl, azido,bromo, chloro, 2-pyridinylsulfanyl, 3-oxo-4-morpholinolinylmethylene,ethoxycarbonyl, 5-methyl-1,3,4-oxadiazol-2-yl, hydroxymethyl,2-hydroxyethylaminomethyl, methylsulfonyloxymethyl; NR³R⁴, wherein R³and R⁴ are each independently selected from acetyl, benzhydryl,1,3-benzodioxol-5-ylmethyl, benzyl, 3-chloro-2-methylphenylsulfonyl,cyclohexyl, cyclohexylmethyl, cyclopropanecarbonyl, ethyl,2-furylcarbonyl, 2-furylmethyl, hydrogen, 2-hydroxyethyl,2-(1H-indol-3-yl)ethyl, isopropyl, methoxy, 2-methoxyethyl, methyl,4-(1-methylimidazolyl)sulfonyl, methylsulfonyl, phenyl,(1S)-phenylethyl, n-propyl, tetrahydro-2-furanylmethyl,trifluoromethylsulfonyl, N-carbethoxypiperidyl; or NR³R⁴ representtogether 4-acetylpiperazinyl, 4-t-butoxycarbonylpiperazinyl,2-(3,4-dihydro-2(1H)isoquinolinyl), (2R,6S)-2,6-dimethylmorpholinyl,(2R)-2,4-dimethyl-1-piperazinyl, 2-hydroxy-3-oxomorpholinyl, imidazolyl,2-methyl-3-oxomorpholinyl, 4-methyl-2-oxopiperazinyl,4-methylpiperazinyl, morpholinyl,(1S,4S)-2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl, 2-oxoimidazolinyl,3-oxomorpholinyl, 3-oxo-1,4-oxazepinyl, 2-oxooxazolinyl, piperazinyl;piperidinyl; pyrrolidinyl; pyrrolidonyl, thiomorpholinyl;1,1-dioxido-thiomorpholinyl; OCONR³R⁴, wherein R³ and R⁴ are eachindependently selected from ethyl, hydrogen or form together with theN-atom to which they are attached morpholinyl; R⁵O, wherein R⁵ isacetyl, benzoyl, benzyl, ethyl, 2-fluoroethyl, 2-furylcarbonyl,hydrogen, isobutyryl, isopropyl, methyl, 2-carbomethoxyphenyl,methylsulfonyl, phenyl, n-propionyl, 3-pyridinyl, 2,2,2-trifluoroethyl.10. The method according to claim 7, wherein the compound is selectedfrom the compounds as defined in claim 3, and also the followingcompounds:3-chloro-N-{5-[2-(diethylamino)ethyl]-1,3,4-thiadiazol-2-yl}-2-methylbenzenesulfonamideN-(5-phenyl-1,3,4-thiadiazol-2-yl)-4-propylbenzenesulfonamide3-chloro-2-methyl-N-(5-phenyl-1,3,4-thiadiazol-2-yl)benzenesulfonamide3-chloro-N-[5-(4-fluoro-3-methylphenyl)-1,3,4-thiadiazol-2-yl]-2-methylbenzenesulfonamide2,4,6-trichloro-N-(5-phenyl-1,3,4-thiadiazol-2-yl)benzenesulfonamideN-(5-phenyl-1,3,4-thiadiazol-2-yl)-1,1′-biphenyl-4-sulfonamide2,4-dichloro-6-methyl-N-(5-phenyl-1,3,4-thiadiazol-2-yl)benzenesulfonamideN-[4-(5-{[(4-propylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)phenyl]acetamideN-[5-(2-chloro-5-nitrophenyl)-1,3,4-thiadiazol-2-yl]-4-propylbenzenesulfonamideN-[5-(2-chlorophenyl)-1,3,4-thiadiazol-2-yl]-4-propylbenzenesulfonamide3-chloro-N-[5-(2-chloro-5-nitrophenyl)-1,3,4-thiadiazol-2-yl]-2-methylbenzenesulfonamide3-chloro-N-[5-(2-chlorophenyl)-1,3,4-thiadiazol-2-yl]-2-methylbenzenesulfonamideN-[4-(5-{[(2,4,6-trichlorophenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)phenyl]acetamide2,4,6-trichloro-N-[5-(2-chloro-5-nitrophenyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide2,4,6-trichloro-N-[5-(2-chlorophenyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamideN-(4-{5-[(1,1′-biphenyl-4-ylsulfonyl)amino]-1,3,4-thiadiazol-2-yl}phenyl)acetamideN-[5-(2-chloro-5-nitrophenyl)-1,3,4-thiadiazol-2-yl]-1,1′-biphenyl-4-sulfonamideN-[5-(2-chlorophenyl)-1,3,4-thiadiazol-2-yl]-1,1′-biphenyl-4-sulfonamideN-[4-(5-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)phenyl]acetamide2,4-dichloro-N-[5-(2-chloro-5-nitrophenyl)-1,3,4-thiadiazol-2-yl]-6-methylbenzenesulfonamide2,4-dichloro-N-[5-(2-chlorophenyl)-1,3,4-thiadiazol-2-yl]-6-methylbenzenesulfonamide2,3,4-trichloro-N-[5-(2-chlorophenyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamideN-[4-(5-{[(4-bromo-2,5-difluorophenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)phenyl]acetamide4,5-dichloro-N-[5-(2-chlorophenyl)-1,3,4-thiadiazol-2-yl]thiophene-2-sulfonamideN-[4-(5-{[(2,4,5-trichlorophenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)phenyl]acetamide3-bromo-5-chloro-N-[5-(2-chlorophenyl)-1,3,4-thiadiazol-2-yl]thiophene-2-sulfonamideN-[4-(5-{[(2,6-dichlorophenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)phenyl]acetamide2,3,4-trichloro-N-{5-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1,3,4-thiadiazol-2-yl}benzenesulfonamideN-[5-(2-chloro-6-fluorophenyl)-1,3,4-thiadiazol-2-yl]-4-propylbenzenesulfonamide4-bromo-N-{5-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1,3,4-thiadiazol-2-yl}-2,5-difluorobenzenesulfonamide4,5-dichloro-N-[5-(2-chloro-6-fluorophenyl)-1,3,4-thiadiazol-2-yl]thiophene-2-sulfonamide4-bromo-5-chloro-N-{5-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1,3,4-thiadiazol-2-yl}thiophene-2-sulfonamide2,4-dichloro-N-[5-(2-chloro-6-fluorophenyl)-1,3,4-thiadiazol-2-yl]-6-methylbenzenesulfonamide4-bromo-N-[5-(2-chloro-6-fluorophenyl)-1,3,4-thiadiazol-2-yl]-2-methylbenzenesulfonamideN-[4-(5-{[(4-bromo-5-chlorothien-2-yl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)phenyl]acetamide.11. A method for inhibiting a human 11-β-hydroxysteroid dehydrogenasetype 1 enzyme, comprising administering to a subject in need thereof aneffective amount of a compound of formula (I):

wherein T is an aryl ring or heteroaryl ring, optionally independentlysubstituted by [R]_(n), wherein n is an integer 0-5, and R is hydrogen,aryl, heteroaryl, a heterocyclic ring, optionally halogenatedC₁₋₆-alkyl, optionally halogenated C₁₋₆-alkoxy, C₁₋₆-alkylsulfonyl,carboxy, cyano, nitro, halogen, amine which is optionally mono- ordi-substituted, amide which is optionally mono- or di-substituted,aryloxy, arylsulfonyl, arylamino, wherein aryl, heteroaryl and aryloxyresidues and heterocyclic rings are further optionally substituted inone or more positions independently of each other by C₁₋₆-acyl,C₁₋₆-alkylthio, cyano, nitro, hydrogen, halogen, optionally halogenatedC₁₋₆-alkyl, optionally halogenated C₁₋₆-alkoxy, amide which isoptionally mono- or di-substituted, (benzoylamino)methyl, carboxy,2-thienylmethylamino or({[4-(2-ethoxy-2-oxoethyl)-1,3-thiazol-2-yl]amino}carbonyl); R¹ ishydrogen or C₁₋₆-alkyl; A₁ and A₂ are a nitrogen atom or C-Z, providedthat A₁ and A₂ have different meanings, wherein: Z is selected from anaryl ring or heteroaryl ring, which is further optionally substituted inone or more positions independently of each other by hydrogen,C₁₋₆-alkyl, halogenated C₁₋₆-alkyl, halogen, C₁₋₆-alkoxy, nitro,C₁₋₆-alkoxycarbonyl, C₁₋₆-alkylsulfonyl, acetylamino or aryloxy, whereinthe aryloxy is further optionally substituted in one or more positionsindependently of each other by hydrogen and halogen; or is X—Y—R²,wherein X is CH₂ or CO; Y is CH₂, CO or a single bond; R² is selectedfrom C₁₋₆-alkyl, azido, arylthio, heteroarylthio, halogen,hydroxymethyl, 2-hydroxyethylaminomethyl, methylsulfonyloxymethyl,3-oxo-4-morpholinolinylmethylene, C₁₋₆-alkoxycarbonyl,5-methyl-1,3,4-oxadiazol-2-yl; NR³R⁴, wherein R³ and R⁴ are eachindependently selected from hydrogen, C₁₋₆-alkyl, optionally halogenatedC₁₋₆-alkylsulfonyl, C₁₋₆-alkoxy, 2-methoxyethyl, 2-hydroxyethyl,1-methylimidazolylsulfonyl, C₁₋₆-acyl, cyclohexylmethyl,cyclopropanecarbonyl, aryl, optionally halogenated arylsulfonyl,furylcarbonyl, tetrahydro-2-furanylmethyl, N-carbethoxypiperidyl, orC₁₋₆-alkyl substituted with one or more aryl, heterocyclic orheteroaryl, or NR³R⁴ represent together heterocyclic systems which areimidazole, piperidine, pyrrolidine, piperazine, morpholine, oxazepine,oxazole, thiomorpholine, 1,1-dioxidothiomorpholine,2-(3,4-dihydro-2(1H)isoquinolinyl), or(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl, which heterocyclic systemsare optionally substituted by C₁₋₆-alkyl, C₁₋₆-acyl, hydroxy, oxo,t-butoxycarbonyl; OCONR³R⁴, wherein R³ and R⁴ are each independentlyselected from hydrogen, C₁₋₆-alkyl or form together with the N-atom towhich they are attached morpholinyl; R⁵O, wherein R⁵ is hydrogen,optionally halogenated C₁₋₆-alkyl, aryl, heteroaryl, C₁₋₆-acyl,C₁₋₆-alkylsulfonyl, arylcarbonyl, heteroarylcarbonyl,2-carbomethoxyphenyl; or a salt, hydrate or solvate thereof.
 12. Themethod according to claim 11, wherein T is selected from5-chloro-1,3-dimethyl-1H-pyrazol-4-yl; 4-chloro-2,3,1-benzoxadiazolyl;5-(dimethylamino)-1-naphthyl; 1-methylimidazol-4-yl; 1-naphthyl;2-naphthyl; 8-quinolinyl; thienyl substituted with one or more of(benzoylamino)methyl, bromo, chloro, 3-isoxazolyl,2-(methylsulfanyl)-4-pyrimidinyl,1-methyl-5-(trifluoromethyl)pyrazol-3-yl, phenylsulfonyl, pyridyl;phenyl substituted with one or more of acetylamino, 3-acetylaminophenyl,3-acetylphenyl, benzeneamino, 1,3-benzodioxol-5-yl, 2-benzofuryl,benzylamino, 3,5-bis(trifluoromethyl)phenyl, bromo, butoxy, carboxy,chloro, 4-carboxyphenyl, 3-chloro-2-cyanophenoxy, 4-chlorophenyl,5-chloro-2-thienyl, cyano, 3,4-dichlorophenyl,({[4-(2-ethoxy-2-oxoethyl)-1,3-thiazol-2-yl]amino}carbonyl), fluoro,5-fluoro-2-methoxyphenyl, 2-furyl, hydrogen, iodo, isopropyl,methanesulfonyl, methoxy, methyl, 4-methyl-1-piperazinyl,4-methyl-1-piperidinyl, 4-methylsulfanylphenyl, 5-methyl-2-thienyl,4-morpholinyl, nitro, 3-nitrophen phenoxy, phenyl, n-propyl, 4-pyridyl,3-pyridylmethylamino, 1-pyrrolidinyl, 2-thienyl, 3-thienyl,2-thienylmethylamino, trifluoromethoxy, 4-trifluoromethoxyphenyl,trifluoromethyl; or R¹ is hydrogen or methyl; A₁ and A₂ are a nitrogenatom or C-Z, provided that A₁ and A₂ have different meanings, wherein: Zis selected from 1-benzothien-3-yl, 3-(2,5-dimethylfuryl), pyridinyl;thienyl optionally substituted with one or more of chloro,methylsulfonyl; phenyl optionally substituted with one or more ofethoxycarbonyl, nitro, fluoro, methyl, methoxy, acetylamino, chloro,4-chlorophenoxy, trifluoromethyl; or is X—Y—R², wherein X is CH₂ or CO;Y is CH₂, CO or a single bond; R² is selected from n-propyl, azido,bromo, chloro, 2-pyridinylsulfanyl, 3-oxo-4-morpholinolinylmethylene,ethoxycarbonyl, 5-methyl-1,3,4-oxadiazol-2-yl, hydroxymethyl,2-hydroxyethylaminomethyl, methylsulfonyloxymethyl; NR³R⁴, wherein R³and R⁴ are each independently selected from acetyl, benzhydryl,1,3-benzodioxol-5-ylmethyl, benzyl, 3-chloro-2-methylphenylsulfonyl,cyclohexyl, cyclohexylmethyl, cyclopropanecarbonyl, ethyl,2-furylcarbonyl, 2-furylmethyl, hydrogen, 2-hydroxyethyl,2-(1H-indol-3-yl)ethyl, isopropyl, methoxy, 2-methoxyethyl, methyl,4-(1-methylimidazolyl)sulfonyl, methylsulfonyl, phenyl,(1S)-phenylethyl, n-propyl, tetrahydro-2-furanylmethyl,trifluoromethylsulfonyl, N-carbethoxypiperidyl; or NR³R⁴ representtogether 4-acetylpiperazinyl, 4-t-butoxycarbonylpiperazinyl,2-(3,4-dihydro-2(1H)isoquinolinyl), (2R,6S)-2,6-dimethylmorpholinyl,(2R)-2,4-dimethyl-1-piperazinyl, 2-hydroxy-3-oxomorpholinyl, imidazolyl,2-methyl-3-oxomorpholinyl, 4-methyl-2-oxopiperazinyl,4-methylpiperazinyl, morpholinyl,(1S,4S)-2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl, 2-oxoimidazolinyl,3-oxomorpholinyl, 3-oxo-1,4-oxazepinyl, 2-oxooxazolinyl, piperazinyl;piperidinyl; pyrrolidinyl; pyrrolidonyl, thiomorpholinyl;1,1-dioxido-thiomorpholinyl; OCONR³R⁴, wherein R³ and R⁴ are eachindependently selected from ethyl, hydrogen or form together with theN-atom to which they are attached morpholinyl; R⁵O, wherein R⁵ isacetyl, benzoyl, benzyl, ethyl, 2-fluoroethyl, 2-furylcarbonyl,hydrogen, isobutyryl, isopropyl, methyl, 2-carbomethoxyphenyl,methylsulfonyl, phenyl, n-propionyl, 3-pyridinyl, 2,2,2-trifluoroethyl.13. The method according to claim 11, wherein the compound is selectedfrom the compounds as defined in claim 3, and also the followingcompounds:3-chloro-N-{5-[2-(diethylamino)ethyl]-1,3,4-thiadiazol-2-yl}-2-methylbenzenesulfonamideN-(5-phenyl-1,3,4-thiadiazol-2-yl)-4-propylbenzenesulfonamide3-chloro-2-methyl-N-(5-phenyl-1,3,4-thiadiazol-2-yl)benzenesulfonamide3-chloro-N-[5-(4-fluoro-3-methylphenyl)-1,3,4-thiadiazol-2-yl]-2-methylbenzenesulfonamide2,4,6-trichloro-N-(5-phenyl-1,3,4-thiadiazol-2-yl)benzenesulfonamideN-(5-phenyl-1,3,4-thiadiazol-2-yl)-1,1′-biphenyl-4-sulfonamide2,4-dichloro-6-methyl-N-(5-phenyl-1,3,4-thiadiazol-2-yl)benzenesulfonamideN-[4-(5-{[(4-propylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)phenyl]acetamideN-[5-(2-chloro-5-nitrophenyl)-1,3,4-thiadiazol-2-yl]-4-propylbenzenesulfonamideN-[5-(2-chlorophenyl)-1,3,4-thiadiazol-2-yl]-4-propylbenzenesulfonamide3-chloro-N-[5-(2-chloro-5-nitrophenyl)-1,3,4-thiadiazol-2-yl]-2-methylbenzenesulfonamide3-chloro-N-[5-(2-chlorophenyl)-1,3,4-thiadiazol-2-yl]-2-methylbenzenesulfonamideN-[4-(5-{[(2,4,6-trichlorophenyi)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)phenyl]acetamide2,4,6-trichloro-N-[5-(2-chloro-5-nitrophenyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide2,4,6-trichloro-N-[5-(2-chlorophenyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamideN-(4-{5-[(1,1′-biphenyl-4-ylsulfonyl)amino]-1,3,4-thiadiazol-2-yl}phenyl)acetamideN-[5-(2-chloro-5-nitrophenyl)-1,3,4-thiadiazol-2-yl]-1,1′-biphenyl-4-sulfonamideN-[5-(2-chlorophenyl)-1,3,4-thiadiazol-2-yl]-1,1′-biphenyl-4-sulfonamideN-[4-(5-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)phenyl]acetamide2,4-dichloro-N-[5-(2-chloro-5-nitrophenyl)-1,3,4-thiadiazol-2-yl]-6-methylbenzenesulfonamide2,4-dichloro-N-[5-(2-chlorophenyl)-1,3,4-thiadiazol-2-yl]-6-methylbenzenesulfonamide2,3,4-trichloro-N-[5-(2-chlorophenyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamideN-[4-(5-{[(4-bromo-2,5-difluorophenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)phenyl]acetamide4,5-dichloro-N-[5-(2-chlorophenyl)-1,3,4-thiadiazol-2-yl]thiophene-2-sulfonamideN-[4-(5-{[(2,4,5-trichlorophenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)phenyl]acetamide3-bromo-5-chloro-N-[5-(2-chlorophenyl)-1,3,4-thiadiazol-2-yl]thiophene-2-sulfonamideN-[4-(5-{[(2,6-dichlorophenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)phenyl]acetamide2,3,4-trichloro-N-{5-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1,3,4-thiadiazol-2-yl}benzenesulfonamideN-[5-(2-chloro-6-fluorophenyl)-1,3,4-thiadiazol-2-yl]-4-propylbenzenesulfonamide4-bromo-N-{5-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1,3,4-thiadiazol-2-yl}-2,5-difluorobenzenesulfonamide4,5-dichloro-N-[5-(2-chloro-6-fluorophenyl)-1,3,4-thiadiazol-2-yl]thiophene-2-sulfonamide4-bromo-5-chloro-N-{5-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1,3,4-thiadiazol-2-yl}thiophene-2-sulfonamide2,4-dichloro-N-[5-(2-chloro-6-fluorophenyl)-1,3,4-thiadiazol-2-yl]-6-methylbenzenesulfonamide4-bromo-N-[5-(2-chloro-6-fluorophenyl)-1,3,4-thiadiazol-2-yl]-2-methylbenzenesulfonamideN-[4-(5-{[(4-bromo-5-chlorothien-2-yl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)phenyl]acetamide.14. The method according to claim 11, wherein the subject is a human.15. A method for treating a 11-β-hydroxysteroid dehydrogenase type 1enzyme-mediated disorder, comprising administering to a subject in needthereof an effective amount of a compound of formula (I)

wherein T is an aryl ring or heteroaryl ring, optionally independentlysubstituted by [R]_(n), wherein n is an integer 0-5, and R is hydrogen,aryl, heteroaryl, a heterocyclic ring, optionally halogenatedC₁₋₆-alkyl, optionally halogenated C₁₋₆-alkoxy, C₁₋₆-alkylsulfonyl,carboxy, cyano, nitro, halogen, amine which is optionally mono- ordi-substituted, amide which is optionally mono- or di-substituted,aryloxy, arylsulfonyl, arylamino, wherein aryl, heteroaryl and aryloxyresidues and heterocyclic rings are further optionally substituted inone or more positions independently of each other by C₁₋₆-acyl,C₁₋₆-alkylthio, cyano, nitro, hydrogen, halogen, optionally halogenatedC₁₋₆-alkyl, optionally halogenated C₁₋₆-alkoxy, amide which isoptionally mono- or di-substituted, (benzoylamino)methyl, carboxy,2-thienylmethylamino or({[4-(2-ethoxy-2-oxoethyl)-1,3-thiazol-2-yl]amino}carbonyl); R¹ ishydrogen or C₁₋₆-alkyl; A₁ and A₂ are a nitrogen atom or C-Z, providedthat A₁ and A₂ have different meanings, wherein: Z is selected from anaryl ring or heteroaryl ring, which is further optionally substituted inone or more positions independently of each other by hydrogen,C₁₋₆-alkyl, halogenated C₁₋₆-alkyl, halogen, C₁₋₆-alkoxy, nitro,C₁₋₆-alkoxycarbonyl, C₁₋₆-alkylsulfonyl, acetylamino or aryloxy, whereinthe aryloxy is further optionally substituted in one or more positionsindependently of each other by hydrogen and halogen; or is X—Y—R²,wherein X is CH₂ or CO; Y is CH₂, CO or a single bond; R² is selectedfrom C₁₋₆-alkyl, azido, arylthio, heteroarylthio, halogen,hydroxymethyl, 2-hydroxyethylaminomethyl, methylsulfonyloxymethyl,3-oxo-4-morpholinolinylmethylene, C₁₋₆-alkoxycarbonyl,5-methyl-1,3,4-oxadiazol-2-yl; NR³R⁴, wherein R³ and R⁴ are eachindependently selected from hydrogen, C₁₋₆-alkyl, optionally halogenatedC₁₋₆-alkylsulfonyl, C₁₋₆-alkoxy, 2-methoxyethyl, 2-hydroxyethyl,1-methylimidazolylsulfonyl, C₁₋₆-acyl, cyclohexylmethyl,cyclopropanecarbonyl, aryl, optionally halogenated arylsulfonyl,furylcarbonyl, tetrahydro-2-furanylmethyl, N-carbethoxypiperidyl, orC₁₋₆-alkyl substituted with one or more aryl, heterocyclic orheteroaryl, or NR³R⁴ represent together heterocyclic systems which areimidazole, piperidine, pyrrolidine, piperazine, morpholine, oxazepine,oxazole, thiomorpholine, 1,1-dioxidothiomorpholine,2-(3,4-dihydro-2(1H)isoquinolinyl), or (1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl, which heterocyclic systems are optionally substituted byC₁₋₆-alkyl, C₁₋₆-acyl, hydroxy, oxo, t-butoxycarbonyl; OCONR³R⁴, whereinR³ and R⁴ are each independently selected from hydrogen, C₁₋₆-alkyl orform together with the N-atom to which they are attached morpholinyl;R⁵O, wherein R⁵ is hydrogen, optionally halogenated C₁₋₆-alkyl, aryl,heteroaryl, C₁₋₆-acyl, C₁₋₆-alkylsulfonyl, arylcarbonyl,heteroarylcarbonyl, 2-carbomethoxyphenyl; or a salt, hydrate or solvatethereof.
 16. The method according to claim 15, wherein the disorder isselected from diabetes, syndrome X, obesity, glaucoma, hyperlipidemia,hyperglycemia, hyperinsulinemia, hypertension, osteoporosis, dementia,depression, virus diseases, inflammatory disorders, andimmuno-modulation, wherein the treatment of hyperglycemia does not causehypoglycemia.
 17. The method according to claim 16, wherein theimmuno-modulation is selected from tuberculosis, lepra, and psoriasis.18. The method according to claim 15, wherein T is selected from5-chloro-1,3-dimethyl-1H-pyrazol-4-yl; 4-chloro-2,3,1-benzoxadiazolyl;5-(dimethylamino)-1-naphthyl; 1-methylimidazol-4-yl; 1-naphthyl;2-naphthyl; 8-quinolinyl; thienyl substituted with one or more of(benzoylamino)methyl, bromo, chloro, 3-isoxazolyl,2-(methylsulfanyl)-4-pyrimidinyl,1-methyl-5-(trifluoromethyl)pyrazol-3-yl, phenylsulfonyl, pyridyl;phenyl substituted with one or more of acetylamino, 3-acetylaminophenyl,3-acetylphenyl, benzeneamino, 1,3-benzodioxol-5-yl, 2-benzofuryl,benzylamino, 3,5-bis(trifluoromethyl)phenyl, bromo, butoxy, carboxy,chloro, 4-carboxyphenyl, 3-chloro-2-cyanophenoxy, 4-chlorophenyl,5-chloro-2-thienyl, cyano, 3,4-dichlorophenyl,({[4-(2-ethoxy-2-oxoethyl)-1,3-thiazol-2-yl]amino}carbonyl), fluoro,5-fluoro-2-methoxyphenyl, 2-furyl, hydrogen, iodo, isopropyl,methanesulfonyl, methoxy, methyl, 4-methyl-1-piperazinyl,4-methyl-1-piperidinyl, 4-methylsulfanylphenyl, 5-methyl-2-thienyl,4-morpholinyl, nitro, 3-nitrophenyl, phenoxy, phenyl, n-propyl,4-pyridyl, 3-pyridylmethylamino, 1-pyrrolidinyl, 2-thienyl, 3-thienyl,2-thienylmethylamino, trifluoromethoxy, 4-trifluoromethoxyphenyl,trifluoromethyl; or R¹ is hydrogen or methyl; A₁ and A₂ are a nitrogenatom or C-Z, provided that A₁ and A₂ have different meanings, wherein: Zis selected from 1-benzothien-3-yl, 3-(2,5-dimethylfuryl), pyridinyl;thienyl optionally substituted with one or more of chloro,methylsulfonyl; phenyl optionally substituted with one or more ofethoxycarbonyl, nitro, fluoro, methyl, methoxy, acetylamino, chloro,4-chlorophenoxy, trifluoromethyl; or is X—Y—R², wherein X is CH₂ or CO;Y is CH₂, CO or a single bond; R² is selected from n-propyl, azido,bromo, chloro, 2-pyridinylsulfanyl, 3-oxo-4-morpholinolinylmethylene,ethoxycarbonyl, 5-methyl-1,3,4-oxadiazol-2-yl, hydroxymethyl,2-hydroxyethylaminomethyl, methylsulfonyloxymethyl; NR³R⁴, wherein R³and R⁴ are each independently selected from acetyl, benzhydryl,1,3-benzodioxol-5-ylmethyl, benzyl, 3-chloro-2-methylphenylsulfonyl,cyclohexyl, cyclohexylmethyl, cyclopropanecarbonyl, ethyl,2-furylcarbonyl, 2-furylmethyl, hydrogen, 2-hydroxyethyl,2-(1H-indol-3-yl)ethyl, isopropyl, methoxy, 2-methoxyethyl, methyl,4-(1-methylimidazolyl)sulfonyl, methylsulfonyl, phenyl,(1S)-phenylethyl, n-propyl, tetrahydro-2-furanylmethyl,trifluoromethylsulfonyl, N-carbethoxypiperidyl; or NR³R⁴ representtogether 4-acetylpiperazinyl, 4-t-butoxycarbonylpiperazinyl,2-(3,4-dihydro-2(1H)isoquinolinyl), (2R,6S)-2,6-dimethylmorpholinyl,(2R)-2,4-dimethyl-1-piperazinyl, 2-hydroxy-3-oxomorpholinyl, imidazolyl,2-methyl-3-oxomorpholinyl, 4-methyl-2-oxopiperazinyl,4-methylpiperazinyl, morpholinyl,(1S,4S)-2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl, 2-oxoimidazolinyl,3-oxomorpholinyl, 3-oxo-1,4-oxazepinyl, 2-oxooxazolinyl, piperazinyl;piperidinyl; pyrrolidinyl; pyrrolidonyl, thiomorpholinyl;1,1-dioxido-thiomorpholinyl; OCONR³R⁴, wherein R³ and R⁴ are eachindependently selected from ethyl, hydrogen or form together with theN-atom to which they are attached morpholinyl; R⁵O, wherein R⁵ isacetyl, benzoyl, benzyl, ethyl, 2-fluoroethyl, 2-furylcarbonyl,hydrogen, isobutyryl, isopropyl, methyl, 2-carbomethoxyphenyl,methylsulfonyl, phenyl, n-propionyl, 3-pyridinyl, 2,2,2-trifluoroethyl.19. The method according to claim 15, wherein the compound is selectedfrom the compounds as defined in claim 3, and also the followingcompounds:3-chloro-N-{5-[2-(diethylamino)ethyl]-1,3,4-thiadiazol-2-yl}-2-methylbenzenesulfonamideN-(5-phenyl-1,3,4-thiadiazol-2-yl)-4-propylbenzenesulfonamide3-chloro-2-methyl-N-(5-phenyl-1,3,4-thiadiazol-2-yl)benzenesulfonamide3-chloro-N-[5-(4-fluoro-3-methylphenyl)-1,3,4-thiadiazol-2-yl]-2-methylbenzenesulfonamide2,4,6-trichloro-N-(5-phenyl-1,3,4-thiadiazol-2-yl)benzenesulfonamideN-(5-phenyl-1,3,4-thiadiazol-2-yl)-1,1′-biphenyl-4-sulfonamide2,4-dichloro-6-methyl-N-(5-phenyl-1,3,4-thiadiazol-2-yl)benzenesulfonamideN-[4-(5-{[(4-propylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)phenyl]acetamideN-[5-(2-chloro-5-nitrophenyl)-1,3,4-thiadiazol-2-yl]-4-propylbenzenesulfonamideN-[5-(2-chlorophenyl)-1,3,4-thiadiazol-2-yl]-4-propylbenzenesulfonamide3-chloro-N-[5-(2-chloro-5-nitrophenyl)-1,3,4-thiadiazol-2-yl]-2-methylbenzenesulfonamide3-chloro-N-[5-(2-chlorophenyl)-1,3,4-thiadiazol-2-yl]-2-methylbenzenesulfonamideN-[4-(5-{[(2,4,6-trichlorophenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)phenyl]acetamide2,4,6-trichloro-N-[5-(2-chloro-5-nitrophenyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide2,4,6-trichloro-N-[5-(2-chlorophenyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamideN-(4-{5-[(1,1′-biphenyl-4-ylsulfonyl)amino]-1,3,4-thiadiazol-2-yl}phenyl)acetamideN-[5-(2-chloro-5-nitrophenyl)-1,3,4-thiadiazol-2-yl]-1,1′-biphenyl-4-sulfonamideN-[5-(2-chlorophenyl)-1,3,4-thiadiazol-2-yl]-1,1′-biphenyl-4-sulfonamideN-[4-(5-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)phenyl]acetamide2,4-dichloro-N-[5-(2-chloro-5-nitrophenyl)-1,3,4-thiadiazol-2-yl]-6-methylbenzenesulfonamide2,4-dichloro-N-[5-(2-chlorophenyl)-1,3,4-thiadiazol-2-yl]-6-methylbenzenesulfonamide2,3,4-trichloro-N-[5-(2-chlorophenyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamideN-[4-(5-{[(4-bromo-2,5-difluorophenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)phenyl]acetamide4,5-dichloro-N-[5-(2-chlorophenyl)-1,3,4-thiadiazol-2-yl]thiophene-2-sulfonamideN-[4-(5-{[(2,4,5-trichlorophenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)phenyl]acetamide3-bromo-5-chloro-N-[5-(2-chlorophenyl)-1,3,4-thiadiazol-2-yl]thiophene-2-sulfonamideN-[4-(5-{[(2,6-dichlorophenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)phenyl]acetamide2,3,4-trichloro-N-{5-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1,3,4-thiadiazol-2-yl}benzenesulfonamideN-[5-(2-chloro-6-fluorophenyl)-1,3,4-thiadiazol-2-yl]-4-propylbenzenesulfonamide4-bromo-N-{5-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1,3,4-thiadiazol-2-yl}-2,5-difluorobenzenesulfonamide4,5-dichloro-N-[5-(2-chloro-6-fluorophenyl)-1,3,4-thiadiazol-2-yl]thiophene-2-sulfonamide4-bromo-5-chloro-N-{5-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1,3,4-thiadiazol-2-yl}thiophene-2-sulfonamide2,4-dichloro-N-[5-(2-chloro-6-fluorophenyl)-1,3,4-thiadiazol-2-yl]-6-methylbenzenesulfonamide4-bromo-N-[5-(2-chloro-6-fluorophenyl)-1,3,4-thiadiazol-2-yl]-2-methylbenzenesulfonamideN-[4-(5-{[(4-bromo-5-chlorothien-2-yl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)phenyl]acetamide.20. The method according to claim 15, wherein the subject is a human.